Phosphatidylinositol 3-kinase inhibitors

ABSTRACT

The present application provides the compounds of formula I or IA 
     
       
         
         
             
             
         
       
         
         
           
             or pharmaceutically acceptable salts, isomers, tautomer, or a mixture thereof, 
             wherein s, t, m, n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are as described herein.

FIELD

The present application relates to novel compounds that selectivelyinhibit the activities of PI3K isoforms and their uses in therapeutictreatments.

BACKGROUND

Cell signaling via 3′-phosphorylated phosphoinositides has beenimplicated in a variety of cellular processes, e.g., malignanttransformation, growth factor signaling, inflammation, and immunity(Rameh et al., J. Biol. Chem., 274:8347-8350, 1999).Phosphatidylinositol 3-kinase (PI 3-kinase or PI3K) is responsible forgenerating these phosphorylated signaling products. PI3K was initiallyidentified as a protein associated with viral oncoproteins and growthfactor receptor tyrosine kinases that phosphorylate phosphatidylinositol(PI) and its phosphorylated derivatives at the 3′-hydroxyl of theinositol ring (Panayotou et al., Trends Cell Biol., 2:358-60, 1992).

Three classes of the PI 3-kinase (PI3K) are proposed based on thesubstrate specificities. Class I PI3Ks phosphorylatephosphatidylinositol (PI), phosphatidylinositol-4-phosphate, andphosphatidylinositol-4,5-biphosphate (PIP₂) to producephosphatidylinositol-3-phosphate (PIP),phosphatidylinositol-3,4-biphosphate, andphosphatidylinositol-3,4,5-triphosphate, respectively. Also, Class IIPI3Ks phosphorylate PI and phosphatidylinositol-4-phosphate, and ClassIII PI3Ks phosphorylate PI.

The initial purification and molecular cloning of PI 3-kinase revealedthat it was a heterodimer consisting of p85 and p110 subunits (Otsu etal., Cell, 65:91-104, 1991; Hiles et al., Cell, 70:419-29, 1992). Later,four distinct Class I PI3Ks were identified and designated as PI3K α, β,δ, and γ isoforms. Each isoform consists of a distinct 110 kDa catalyticsubunit and a regulatory subunit. The catalytic subunits of PI3K α, β,and δ (i.e., p110α, p110β, and p110δ, respectively) interacts,individually, with the same regulatory subunit p85, whereas thecatalytic subunit of PI3K γ (p110γ) interacts with a distinct regulatorysubunit p101.

Studies have also showed that each PI3K isoform has distinct expressionpattern. For example, PIK3CA which encodes PI3Kα is frequently mutatedin human cancers (Engelman, Nat. Rev. Cancer, 9: 550-562, 2009). Also,PI3Kδ is generally expressed in hematopoietic cells. Moreover, PI3Kisoforms are shown to be associated with proliferation or survivalsignaling in cancers, inflammatory, or autoimmune diseases. As each PI3Kisoform has different biological function, PI3K isoforms are potentialtargets to treat cancer or disorder (U.S. Pat. Nos. 6,800,620;8,435,988; 8,673,906; US Patent Application Publication No. US2013/0274253).

Therefore, there is a need for developing therapeutic agents thatinhibit PI3K isoforms to treat diseases, disorders, or conditions thatare mediated by PI3K.

SUMMARY

The present application provides novel compounds that are inhibitors ofPI3K isoforms. The application also provides compositions, includingpharmaceutical compositions, kits that include the compounds, andmethods of using and making the compounds. The compounds provided hereinare useful in treating diseases, disorders, or conditions that aremediated by PI3K isoforms. The application also provides compounds foruse in therapy. The application further provides compounds for use in amethod of treating a disease, disorder, or condition that is mediated byPI3K isoforms. Moreover, the application provides uses of the compoundsin the manufacture of a medicament for the treatment of a disease,disorder or condition that is mediated by PI3K isoforms. In typicalembodiments, provided are compounds of formula I or IA:

-   wherein n is 1, 2, 3 or 4;-   m is 1, 2, 3 or 4;-   s is 1 or 2;-   t is 1 or 2;-   each R¹ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a),    —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered    heteroaryl containing 1 to 4 heteroatoms selected from the group    consisting of N, O, and S, and 4-10 membered heterocyclyl containing    1 to 4 heteroatoms selected from the group consisting of N, O, and    S;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R¹⁰⁰;-   R² is selected from hydrogen, halo, cyano, hydroxy, amino,    —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b),    —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a),    NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl    containing 1 to 4 heteroatoms selected from the group consisting of    N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4    heteroatoms selected from the group consisting of N, O, and S;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R¹⁰¹;-   R³ is selected from C₆₋₁₀ aryl, 5-10 membered heteroaryl containing    1 to 4 heteroatoms selected from the group consisting of N, O, and    S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms    selected from the group consisting of N, O, and S;    -   wherein each C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R¹⁰²;-   R⁴ is selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, acyl, C₃₋₈ cycloalkyl and C₁₋₆ alkyl sulfonyl;-   each R⁵ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a),    —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered    heteroaryl containing 1 to 4 heteroatoms selected from the group    consisting of N, O, and S, and 4-10 membered heterocyclyl containing    1 to 4 heteroatoms selected from the group consisting of N, O, and    S;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R¹⁰³;-   each R⁶ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a),    —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆    alkenyl or C₂₋₆ alkynyl;-   R⁷ is selected from hydrogen, halo, cyano, hydroxy, amino,    —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b),    —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a),    —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₈ cycloalkyl;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl is        optionally substituted with one to four R¹⁰²;-   each R^(a) and R^(b) is independently selected from hydrogen, C₁₋₆    alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, is        optionally substituted with one to four R²⁰⁰;-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ is independently selected from    hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl,    —C(O)R^(c), —C(O)OR^(c), —C(O)NR^(c)R^(d), —N(R^(c))C(O)R^(d),    —S(O)NR^(c)R^(d), —S(O)₂NR^(c)R^(d), —S(O)R^(c), —S(O)₂R^(c),    —NR^(c)R^(d), —OR^(c), —SR^(d), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and    4-10 membered heterocyclyl;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R²⁰¹;    -   each R^(c) and R^(d) is independently selected from hydrogen,        C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;-   each R²⁰⁰ and R²⁰¹ is independently selected from hydrogen, halo,    cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(e), —C(O)OR^(e),    —C(O)NR^(e)R^(f), —N(R^(e))C(O)R^(f), —S(O)NR^(e)R^(f),    —S(O)₂NR^(e)R^(f), —S(O)R^(e), —S(O)₂R^(e), —NR^(e)R^(f), —OR^(e),    —SR^(e), C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;    -   each R^(e) and R^(f) is independently selected from hydrogen,        C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In certain embodiments, the PI3K inhibitors are the compounds selectedfrom Table 1, a pharmaceutically acceptable salt, isomer, or a mixturethereof. In additional embodiments, the compound is an (S)-enantiomer.In other embodiments, the compound is an (R)-enantiomer. In otheradditional embodiments, the compound is an atropisomer.

The application also provides a pharmaceutical composition thatcomprises a compound of formula (I), a pharmaceutically acceptable salt,isomer, or a mixture thereof, together with at least onepharmaceutically acceptable vehicle. Examples of a pharmaceuticallyacceptable vehicle may be selected from carriers, adjuvants, andexcipients.

Further provided herein is a method of treating a disease, disorder, orcondition in a human in need thereof by administering to the human atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt, isomer, or a mixture thereof. Furtherprovided is a compound of formula (I) for use in a method of treating adisease, disorder or condition that is mediated by PI3K isoforms. Theapplication also provides the use of a compound of formula (I) in themanufacture of a medicament for the treatment of a disease, disorder orcondition that is mediated by PI3K isoforms. In certain embodiments, thedisease, disorder, or condition is associated or mediated by PI3K. Insome embodiments, the disease, disorder, or condition is an inflammatorydisorder. In other embodiments, the disease, disorder, or condition is acancer.

Also provided herein is a method of inhibiting the activity of aphosphatidylinositol 3-kinase polypeptide by contacting the polypeptidewith a compound of formula (I) or a pharmaceutically acceptable salt,isomer, or a mixture thereof.

Further provided is a method of inhibiting excessive or destructiveimmune reactions, comprising administering an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt, isomer,or a mixture thereof.

Also provided is a method of inhibiting growth or proliferation ofcancer cells comprising contacting the cancer cells with an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt, isomer, or a mixture thereof.

Also provided is a kit that includes a compound of formula (I) or apharmaceutically acceptable salt, isomer, or a mixture thereof. The kitmay further comprise a label and/or instructions for use of the compoundin treating a disease, disorder, or condition in a human in needthereof. In some embodiments, the disease, disorder, or condition may beassociated or mediated by PI3K activity.

Also provided are articles of manufacture that include a compound offormula (I) or a pharmaceutically acceptable salt, isomer, or a mixturethereof, and a container. In one embodiment, the container may be avial, jar, ampoule, preloaded syringe, or an intravenous bag.

DETAILED DESCRIPTION

The following description sets forth exemplary methods, parameters andthe like. Such description is not intended as a limitation on the scopeof the present application but is instead provided as exemplaryembodiments.

As used herein, the following words, phrases and symbols are generallyintended to have the meanings as set forth below, except to the extentthat the context in which they are used indicates otherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line drawn through a line in a structureindicates a point of attachment of a group. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written or named.

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount ±10%. In other embodiments, the term “about” includes theindicated amount ±5%. In certain other embodiments, the term “about”includes the indicated amount ±1%. Also, to the term “about X” includesdescription of “X”. Also, the singular forms “a” and “the” includeplural references unless the context clearly dictates otherwise. Thus,e.g., reference to “the compound” includes a plurality of such compoundsand reference to “the assay” includes reference to one or more assaysand equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆alkyl), or 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl). Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having aspecific number of carbons is named, all geometric isomers having thatnumber of carbons may be encompassed; thus, for example, “butyl”includes n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” includesn-propyl and isopropyl.

“Alkenyl” refers to an aliphatic group containing at least onecarbon-carbon double bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkenyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl).Examples of alkenyl groups include ethenyl, propenyl, butadienyl(including 1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an aliphatic group containing at least onecarbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkynyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl).The term “alkynyl” also includes those groups having one triple bond andone double bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

“Acyl” refers to a group —C(═O)R, wherein R is hydrogen, alkyl,cycloalkyl, heterocycloalkyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein. Examples of acylinclude formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl,and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group—C(═O)NR^(y)R^(z) and an “N-amido” group which refers to the group—NR^(y)C(═O)R^(z), wherein R^(y) and R^(z) are independently selectedfrom the group consisting of hydrogen, alkyl, aryl, haloalkyl, orheteroaryl; each of which may be optionally substituted.

“Amino” refers to the group —NR^(y)R^(z) wherein R^(y) and R^(z) areindependently selected from the group consisting of hydrogen, alkyl,haloalkyl, aryl, or heteroaryl; each of which may be optionallysubstituted.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groupsinclude phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, doesnot encompass or overlap in any way with heteroaryl defined below. Ifone or more aryl groups are fused with a heteroaryl ring, the resultingring system is heteroaryl.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” refers to a saturated or partially saturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e. the cyclic group having at least one alkenyl). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms(i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkyl includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃).

“Heteroalkyl” refers to an alkyl group in which one or more of thecarbon atoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatomic group. By way ofexample, 1, 2 or 3 carbon atoms may be independently replaced with thesame or different heteroatomic group. Heteroatomic groups include, butare not limited to, —NR—, —O—, —S—, —S(O)—, —S(O)₂—, and the like, whereR is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl orheterocycloalkyl, each of which may be optionally substituted. Examplesof heteroalkyl groups include —OCH₃, —CH₂OCH₃, —SCH₃, —CH₂SCH₃, —NRCH₃,and —CH₂NRCH₃, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl,or heteroaryl, each of which may be optionally substituted. As usedherein, heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms,or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1heteroatom.

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings, or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. As usedherein, heteroaryl include 1 to 20 ring carbon atoms, 3 to 12 ringcarbon atoms, or 3 to 8 carbon ring atoms; and 1 to 5 heteroatoms, 1 to4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1ring heteroatom independently selected from nitrogen, oxygen, andsulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl,pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does notencompass or overlap with aryl as defined above.

“Heterocycloalkyl” refers to a saturated or unsaturated cyclic alkylgroup, with one or more ring heteroatoms independently selected fromnitrogen, oxygen and sulfur. The term “heterocycloalkyl” includesheterocycloalkenyl groups (i.e. the heterocycloalkyl group having atleast one alkenyl). A heterocycloalkyl may be a single ring or multiplerings wherein the multiple rings may be fused, bridged, or spiro. Asused herein, heterocycloalkyl has 2 to 20 ring carbon atoms, 2 to 12ring carbon atoms, 2 to 10 ring carbon atoms, 2 to 8 ring carbon atoms,3 to 12 ring carbon atoms, 3 to 8 ring carbon atoms, or 3 to 6 ringcarbon atoms; having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatomindependently selected from nitrogen, sulfur or oxygen. Examples ofheterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl,oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Oxo” refers to the group (═O) or (O).

“Sulfonyl” refers to the group —S(O)₂R, where R is alkyl, haloalkyl,cycloalkyl, heterocycloalkyl, heteroaryl, or aryl. Examples of sulfonylare methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

Certain commonly used alternative chemical names may be used. Forexample, a divalent group such as a divalent “alkyl” group, a divalent“aryl” group, etc., may also be referred to as an “alkylene” group or an“alkylenyl” group, an “arylene” group or an “arylenyl” group,respectively. Also, unless indicated explicitly otherwise, wherecombinations of groups are referred to herein as one moiety, e.g.arylalkyl, the last mentioned group contains the atom by which themoiety is attached to the rest of the molecule.

The terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” refers to any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo,haloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxy,hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid,alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Byway of example, there may be one, two, three, four, five, or sixsubstituents. Polymers or similar indefinite structures arrived at bydefining substituents with further substituents appended ad infinitum(e.g., a substituted aryl having a substituted alkyl which is itselfsubstituted with a substituted aryl group, which is further substitutedby a substituted heteroalkyl group, etc.) are not intended for inclusionherein. Unless otherwise noted, the maximum number of serialsubstitutions in compounds described herein is three. For example,serial substitutions of substituted aryl groups with two othersubstituted aryl groups are limited to substituted aryl (substitutedaryl) substituted aryl. Similarly, the above definitions are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluorines or heteroaryl groups having two adjacentoxygen ring atoms). Such impermissible substitution patterns are wellknown to the skilled artisan. When used to modify a chemical group, theterm “substituted” may describe other chemical groups defined herein.For example, the term “substituted aryl” includes, but is not limitedto, “alkylaryl.” Unless specified otherwise, where a group is describedas optionally substituted, any substituents of the group are themselvesunsubstituted.

In some embodiments, the term “substituted alkyl” refers to an alkylgroup having one or more substituents including hydroxyl, halo, alkoxy,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In additionalembodiments, “substituted cycloalkyl” refers to a cycloalkyl grouphaving one or more substituents including alkyl, haloalkyl,heterocycloalkyl, aryl, heteroaryl, alkoxy, halo, hydroxyl; “substitutedaryl” refers to an aryl group having one or more substituents includinghalo, alkyl, haloalkyl, heterocycloalkyl, heteroaryl, alkoxy, and cyano,and “substituted sulfonyl” refers to a group —S(O)₂R, in which R issubstituted with one or more substituents of alkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl. In other embodiments, the one ormore substituents may be further substituted with halo, alkyl,haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,each of which is substituted. In other embodiments, the substituents maybe further substituted with halo, alkyl, haloalkyl, alkoxy, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl, each of which is unsubstituted.

List of Abbreviations and Acronyms

Abbreviation Meaning ° C. Degree Celsius Ac Acetyl aq. Aqueous ATPAdenosine triphosphate br Broad BSA Bovine serum albumin CbzCarboxybenzyl COD Cyclooctadiene COPD Chronic obstructive pulmonarydisease d Doublet DCE Dichloroethene DCM Dichloromethane dd Doublet ofdoublets DIEA Diisopropylethylamine DMF Dimethylformamide DMSODimethylsulfoxide dt Doublet-triplet DTT Dithiothreitol EC₅₀ The halfmaximal effective concentration eq Equivalents ES/MS Electrospray massspectrometry Et Ethyl FBS Fetal bovine serum g Grams HEPES2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid HPLC Highpressure liquid chromatography hr or h or hrs Hours Hz Hertz IBDInflammatory bowel disease i-pr Isopropyl J Coupling constant (MHz)Kg/kg Kilogram LCMS Liquid chromatography-mass spectrometry LPSLipopolysaccharide M Molar m multiplet M+ Mass peak M + H+ Mass peakplus hydrogen Me Methyl mg Milligram MHz Megahertz ml/mL Milliliter mMMillimolar mmol Millimole MOPS 3-Morpholinopropane-1-sulfonic acid MSMass spectroscopy Ms Mesyl nBu/Bu Butyl nL Nanoliter nm Nanometer NMRNuclear magnetic resonance NMP N-methylpyrrolidinone NP-40 Nonylphenoxypolyethoxylethanol Pd—C/Pd/C Palladium on Carbon Ph Phenyl qQuartet q.s. Quantity sufficient to achieve a stated function RP Reversephase rt Room temperature s Singlet sat. Saturated t Triplet TEATriethylamine Tf Trifluoromethanesulfonyl TFA Trifluoroacetic acid THFTetrahydrofuran TR-FRET Time-resolved fluorescence energy transfer δChemical shift (ppm) μL/μl Microliter μM MicromolarCompounds

The present application provides compounds that function as inhibitorsof PI3K isoforms. In one aspect, provided are the compounds having thestructure of formula I or IA:

-   wherein n is 1, 2, 3 or 4;-   m is 1, 2, 3 or 4;-   s is 1 or 2;-   t is 1 or 2;-   each R¹ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a),    —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered    heteroaryl containing 1 to 4 heteroatoms selected from the group    consisting of N, O, and S, and 4-10 membered heterocyclyl containing    1 to 4 heteroatoms selected from the group consisting of N, O, and    S;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R¹⁰⁰;-   R² is selected from hydrogen, halo, cyano, hydroxy, amino,    —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b),    —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a),    —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl    containing 1 to 4 heteroatoms selected from the group consisting of    N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4    heteroatoms selected from the group consisting of N, O, and S;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R¹⁰¹;-   R³ is selected from C₆₋₁₀ aryl, 5-10 membered heteroaryl containing    1 to 4 heteroatoms selected from the group consisting of N, O, and    S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms    selected from the group consisting of N, O, and S;    -   wherein each C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R¹⁰²;-   R⁴ is selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, acyl, C₃₋₈ cycloalkyl and C₁₋₆ alkyl sulfonyl;-   each R⁵ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a),    —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered    heteroaryl containing 1 to 4 heteroatoms selected from the group    consisting of N, O, and S, and 4-10 membered heterocyclyl containing    1 to 4 heteroatoms selected from the group consisting of N, O, and    S;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R¹⁰³;-   each R⁶ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a),    —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆    alkenyl or C₂₋₆ alkynyl;-   each R^(a) and R^(b) is independently selected from hydrogen, C₁₋₆    alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, is        optionally substituted with one to four R²⁰⁰;-   each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ is independently selected from    hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl,    —C(O)R^(c), —C(O)OR, —C(O)NR^(c)R^(d), —N(R^(c))C(O)R^(d),    —S(O)NR^(c)R^(d), —S(O)₂NR^(c)R^(d), —S(O)R^(c), —S(O)₂R,    —NR^(c)R^(d), —OR^(c), —SR^(d), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and    4-10 membered heterocyclyl;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10        membered heterocyclyl is optionally substituted with one to four        R²⁰¹;    -   each R^(c) and R^(d) is independently selected from hydrogen,        C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;-   each R²⁰⁰ and R²⁰¹ is independently selected from hydrogen, halo,    cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(e), —C(O)OR^(e),    —C(O)NR^(e)R^(f), —N(R^(e))C(O)R^(f), —S(O)NR^(e)R^(f),    —S(O)₂NR^(e)R^(f), —S(O)R^(e), —S(O)₂R^(e), —NR^(e)R^(f), —OR^(e),    —SR^(e), C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;    -   each R^(e) and R^(f) is independently selected from hydrogen,        C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IB:

-   wherein n, s, m, t, R¹, R², R⁴, R⁵ and R⁶ are as defined above;-   represents a single or double bond;-   X¹ is N or C;-   each X², X³, X⁴ and X⁵ is independently selected from S, O, CR¹⁰ and    NR¹¹;    -   wherein each R¹⁰ is independently selected from hydrogen, halo,        cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b),        —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b),        —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b),        —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to        4 heteroatoms selected from the group consisting of N, O, and S,        and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms        selected from the group consisting of N, O, and S;        -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈            cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10            membered heterocyclyl is optionally substituted with one to            four R¹⁰⁴;    -   wherein each R¹¹ is independently selected from absent,        hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b),        —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b),        —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b),        —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to        4 heteroatoms selected from the group consisting of N, O, and S,        and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms        selected from the group consisting of N, O, and S;    -   alternatively, one R¹⁰ and one R¹¹ group, together with the        atoms to which they are attached form a five, six or seven        membered fused or bridged ring;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IC:

-   wherein n, s, m, t, R¹, R², R⁴ and R⁵ are as defined above;-   each R¹³ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b),    —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a),    —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered    heteroaryl containing 1 to 4 heteroatoms selected from the group    consisting of N, O, and S, and 4-10 membered heterocyclyl containing    1 to 4 heteroatoms selected from the group consisting of N, O, and    S;-   each R^(a) and R^(b) is independently selected from hydrogen, C₁₋₆    alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;    -   wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, is        optionally substituted with one to four R²⁰⁰;-   each R²⁰⁰ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(e), —C(O)OR^(e),    —C(O)NR^(e)R^(f), —N(R^(e))C(O)R^(f), —S(O)NR^(e)R^(f),    —S(O)₂NR^(e)R^(f), —S(O)R^(e), —S(O)₂R^(e), —NR^(e)R^(f), —OR^(e),    —SR^(e), C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;    -   each R^(e) and R^(f) is independently selected from hydrogen,        C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula ID:

-   wherein n, s, m, R¹, R², R⁴, R⁵, and R¹³ are as defined above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IE:

-   wherein n, s, m, R¹, R², R⁴, R⁵, X¹, X², X³, X⁴ and X⁵ are as    defined above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IF:

-   wherein n, s, m, t, R¹, R², R⁴, R⁵, and R¹³ are as defined above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IG:

-   wherein n, s, m, R¹, R², R⁴, R⁵, and R¹³ are as defined above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IH:

-   wherein n, s, m, R¹, R², R⁴, R⁵, X¹, X², X³, X⁴ and X⁵ are as    defined above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IJ:

-   wherein n, s, m, t, R¹, R², R⁴, R⁵, and R¹³ are as defined above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula IK:

-   wherein n, s, m, R¹, R², R⁴, R⁵, and R¹³ are as defined above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In another aspect, provided are compounds of Formula (IL) or (IM)

-   wherein n, s, m, R¹, R², R⁴, R⁵, and R⁷ are as defined above;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In certain embodiments, provided is a compound of Formula I, wherein R³is

-   wherein t is 1 or 2;-   each R¹³ is independently selected from hydrogen, halo, cyano,    hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(a), —C(O)OR^(b),    —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b),    —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a),    —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,    C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms    selected from the group consisting of N, O, and S, and 4-10 membered    heterocyclyl containing 1 to 4 heteroatoms selected from the group    consisting of N, O, and S;-   or a pharmaceutically acceptable salt, isomer, or a mixture thereof.

In certain embodiments, provided is a compound of Formula IE or IH, or apharmaceutically acceptable salt, isomer, or a mixture thereof; whereinthe substituent

is selected from:

One of skill in the art understands that t=1 for compounds having onlyone atom available for substitution.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK, IL or IM, wherein R¹ is selected fromhydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl,fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,difluoroethyl and trifluoroethyl; or a pharmaceutically acceptable salt,isomer, or a mixture thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK, IL or IM, wherein R¹ is fluoro or chloro; ora pharmaceutically acceptable salt, isomer, or a mixture thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK, IL or IM, wherein R² is C₁₋₆ alkyl, C₃₋₈cycloalkyl, 5-6 membered heteroaryl containing 1 to 3 heteroatomsselected from the group consisting of N, O, and S, and 4-6 memberedheterocyclyl containing 1 to 4 heteroatoms selected from the groupconsisting of N, O, and S; wherein each C₁₋₆ alkyl, C₃₋₈ cycloalkyl, 5-6membered heteroaryl and 4-6 membered heterocyclyl is optionallysubstituted with one to four R¹⁰¹; or a pharmaceutically acceptablesalt, isomer, or a mixture thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK, IL or IM, wherein R² is selected fromhydrogen, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, furanyl, tetrahydrofuranyl, oxetanyl, and cyclopropyl; or apharmaceutically acceptable salt, isomer, or a mixture thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK, IL or IM, wherein R⁴ is selected fromhydrogen and methyl; or a pharmaceutically acceptable salt, isomer, or amixture thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK, IL or IM, wherein R⁵ is selected fromhydrogen, methyl, ethyl, trifluoromethyl, carboxamide, cyano,piperazinyl, cyclopropyl, phenyl and triazolyl; or a pharmaceuticallyacceptable salt, isomer, or a mixture thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK, IL or IM, wherein R¹ is selected fromhydrogen or a substituent selected from the table below:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK, IL or IM, wherein R² is selected fromhydrogen or a substituent selected from the table below:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound of Formula I, wherein R³is selected from hydrogen or a substituent selected from the tablebelow:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound of Formula I, IA, IB, IC,ID, IE, IF, IG, IH, IJ, IK, IL or IM, wherein R⁵ is selected fromhydrogen or a substituent selected from the table below:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound selected from Table A, ora pharmaceutically acceptable salt, isomer, or a mixture thereof:

TABLE A Example Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

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89

90

91

92

93

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95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

198

199

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202

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211

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237

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239

240

241

242

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260

261

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265

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267

268

269

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271

272

273

274

275

276

277

278

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280

281

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286

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291

292

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295

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298

299

300

301

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304

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308

309

310

311

312

313

314

315

316

317

318

319

320

321

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323

329

330

331

332

333

334

335

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343

344

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347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

In certain embodiments, provided is a compound selected from Table B, ora pharmaceutically acceptable salt, isomer, or a mixture thereof:

TABLE B Example Image 149

150

151

152

153

154

155

156

157

247

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

387

388

389

390

391

392

393

394

The present application provides pharmaceutically acceptable salts,hydrates, solvates, isomers, tautomers, stereoisomers, enantiomers,racemates, atropisomers, polymorphs, prodrugs, or a mixture thereof, ofthe compounds described herein. The terms “a compound of the presentapplication,” “a compound described herein,” “a compound of any of theformulae described herein,” or variant thereof refer to a compoundhaving the structure of any of the formulae, I, IA, IB, IC, ID, IE, IF,IG, IH, IJ, IK, IL and IM.). In some embodiments, compounds of thepresent application are Compounds 1-363 as described herein.

“Pharmaceutically acceptable” or “physiologically acceptable” refer tocompounds, salts, compositions, dosage forms and other materials whichare useful in preparing a pharmaceutical composition that is suitablefor veterinary or human pharmaceutical use. “Pharmaceutically acceptablesalts” or “physiologically acceptable salts” refer to salts ofpharmaceutical compounds that retain the biological effectiveness andproperties of the underlying compound, and which are not biologically orotherwise undesirable. There are acid addition salts and base additionsalts. Pharmaceutically acceptable acid addition salts may be preparedfrom inorganic and organic acids. Acids and bases useful for reactionwith an underlying compound to form pharmaceutically acceptable salts(acid addition or base addition salts respectively) are known to one ofskill in the art. Similarly, methods of preparing pharmaceuticallyacceptable salts from an underlying compound (upon disclosure) are knownto one of skill in the art and are disclosed in for example, Berge, atal. Journal of Pharmaceutical Science, January 1977 vol. 66, No. 1, andother sources. If the compounds described herein are obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Saltsderived from organic acids include acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, p-toluene-sulfonic acid, salicylic acid, and the like. Saltsderived from mineral acids include, hydrochloride, hydrobromide,hydroiodide, nitrate, phosphate, and sulfate. Likewise, pharmaceuticallyacceptable base addition salts can be prepared from inorganic andorganic bases. Salts derived from inorganic bases include, by way ofexample only, sodium, potassium, lithium, ammonium, calcium andmagnesium salts. Salts derived from organic bases include, but are notlimited to, salts of primary, secondary and tertiary amines, such asalkyl amines (i.e., NH₂(alkyl)), dialkyl amines (i.e., HN(alkyl)₂),trialkyl amines (i.e., N(alkyl)₃), substituted alkyl amines (i.e.,NH₂(substituted alkyl)), di(substituted alkyl) amines (i.e.,HN(substituted alkyl)₂), tri(substituted alkyl) amines (i.e.,N(substituted alkyl)₃), alkenyl amines (i.e., NH₂(alkenyl)), dialkenylamines (i.e., HN(alkenyl)₂), trialkenyl amines (i.e., N(alkenyl)₃),substituted alkenyl amines (i.e., NH₂(substituted alkenyl)),di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)₂),tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)₃, mono-,di- or tri-cycloalkyl amines (i.e., NH₂(cycloalkyl), HN(cycloalkyl)₂,N(cycloalkyl)₃), mono-, di- or tri-arylamines (i.e., NH₂(aryl),HN(aryl)₂, N(aryl)₃), or mixed amines, etc. Specific examples ofsuitable amines include, by way of example only, isopropylamine,trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine,morpholine, N-ethylpiperidine, and the like.

“Isomers” refers to compounds that have the same molecular formula. Asused herein, the term isomers include double bond isomers, racemates,stereoisomers, enantiomers, diastereomers, and atropisomers. Singleisomers, such as enantiomers or diastereomers, can be obtained byasymmetric synthesis or by resolution of a mixture of isomers.Resolution of a mixture of isomers (e.g. racemates) maybe accomplished,for example, by conventional methods such as crystallization in thepresence of a resolving agent, or chromatography, using, for example achiral high pressure liquid chromatography (HPLC) column. “Double bondisomers” refer to Z- and E-forms (or cis- and trans-forms) of thecompounds with carbon-carbon double bonds.

“Atropisomers” refers to conformational stereoisomers which occur whenrotation about a single bond in the molecule is prevented, or greatlyhindered, as a result of steric interactions with other parts of themolecule and the substituents at both ends of the single bond areasymmetrical, i.e., they do not require a stereocenter. Where therotational barrier about the single bond is high enough, andinterconversion between conformations is slow enough, separation andisolation of the isomeric species may be permitted. Atropisomers may beseparated by the methods well known in the art. Unless otherwiseindicated, the description is intended to include individualatropisomers as well as mixtures. Also, as understood by those skilledin the art, the atropisomers may be represented by the same chemicalname with different atropisomer designations. By way of example, thebelow structures are atropisomers of compound 230(4-(1-(5,8-difluoroquinolin-4-yl)-4-(oxazol-2-yl)-2-propyl-1H-benzo[d]imidazol-6-yl)morpholine).

Compounds of the invention are named using Chembiodraw Ultra (version14).

“Racemates” refers to a mixture of enantiomers.

“Stereoisomers” or “stereoisomeric forms” refer to compounds that differin the chirality of one or more stereocenters. Stereoisomers includeenantiomers and diastereomers. The compounds may exist in stereoisomericform if they possess one or more asymmetric centers or a double bondwith asymmetric substitution and, therefore, can be produced asindividual stereoisomers or as mixtures. Unless otherwise indicated, thedescription is intended to include individual stereoisomers as well asmixtures. The methods for the determination of stereochemistry and theseparation of stereoisomers are well-known in the art (see, e.g.,Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wileyand Sons, New York, 1992).

“Tautomers” or “tautomeric forms” refer to alternate forms of a compoundthat differ in the position of a proton, such as enol-keto andimine-enamine tautomers, or heteroaryls such as pyrazoles, imidazoles,benzimidazoles, triazoles, and tetrazoles.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds of any of the formulae describedherein are also provided. Hydrates of the compounds of any of theformulae are also provided.

A “prodrug” is defined in the pharmaceutical field as a biologicallyinactive derivative of a drug that upon administration to the human bodyis converted to the biologically active parent drug according to somechemical or enzymatic pathway. A prodrug is thus a covalently modifiedanalog or latent form of a therapeutically active compound. Non-limitingexamples of prodrugs include ester moieties, quaternary ammoniummoieties, glycol moieties, and the like.

In any one of the foregoing embodiments, the compound described hereinor a pharmaceutically acceptable salt thereof is an (S)-enantiomer. Inany one of the foregoing embodiments, the compound described herein or apharmaceutically acceptable salt thereof is an (R)-enantiomer. In anyone of the foregoing embodiments, the compound described herein or apharmaceutically acceptable salt thereof is an atropisomer.

The application also provides a composition containing a mixture ofenantiomers of the compound or a pharmaceutically acceptable saltthereof. In one embodiment, the mixture is a racemic mixture. In otherembodiments, the composition comprises the (S)-enantiomer of a compoundin excess of the corresponding (R)-enantiomer of the compound. In someembodiments, the composition contains the (S)-enantiomer of the compoundand is substantially free of its corresponding (R)-enantiomer. Incertain embodiments, a composition substantially free of the(R)-enantiomer has less than or about 40%, 35%, 30%, 25%, 20%, 15%, 10%,5%, 1%, 0.05%, or 0.01% of the (R)-enantiomer. In other embodiments, thecomposition containing the (S)-enantiomer of a compound or apharmaceutically acceptable salt thereof, predominates over itscorresponding (R)-enantiomer by a molar ratio of at least or about 9:1,at least or about 19:1, at least or about 40:1, at least or about 80:1,at least or about 160:1, or at least or about 320:1.

The composition containing a compound according to any of the formulaedescribed herein or a pharmaceutically acceptable salt thereof, may alsocontain the compound in enantiomeric excess (e.e.). By way of example, acompound with 95% (S)-isomer and 5% (R)-isomer will have an e.e. of 90%.In some embodiments, the compound has an e.e. of at least or about 60%,75%, 80%, 85%, 90%, 95%, 98% or 99%.

In any one of the foregoing embodiments, the compound or apharmaceutically acceptable salt thereof, is an atropisomer. Anotherembodiment provides the composition containing a mixture of atropisomersof the compound or a pharmaceutically acceptable salt thereof. By way ofexample, a compound with 95% of one atropisomer and 5% of the otheratropisomers. In some embodiments, a compound with about 90, 80, 70, 60,50, 40, 30, 20, or 10% of one atropisomer and 10, 20, 30, 40, 50, 60,70, 80, or 90%, respectively, of the other atropisomers.

The application also provides the free base forms of the compoundsdescribed herein. In certain embodiments, provided herein are theenantiomers, (R) or (S), of the compounds of the formulae describedherein. In other embodiments, provided herein are the atropisomers ofthe compounds of the formulae described herein.

The application further provides compositions comprising the compoundsdescribed herein or a pharmaceutically acceptable salt, isomer, prodrug,or solvate thereof. The composition may include racemic mixtures,mixtures containing an enantiomeric excess of one enantiomer or singlediastereomers or diastereomeric mixtures. All such isomeric forms ofthese compounds are expressly included herein, the same as if each andevery isomeric form were specifically and individually listed.

In certain embodiments, provided herein are also polymorphs, such ascrystalline and amorphous forms, of the compounds described herein. Insome embodiments, provided are also chelates, non-covalent complexes,and mixtures thereof, of the compounds of the formula described hereinor pharmaceutically acceptable salts, prodrugs, or solvates thereof. A“chelate” is formed by the coordination of a compound to a metal ion attwo (or more) points. A “non-covalent complex” is formed by theinteraction of a compound and another molecule wherein a covalent bondis not formed between the compound and the molecule. For example,complexation can occur through van der Waals interactions, hydrogenbonding, and electrostatic interactions (also called ionic bonding).

In certain embodiments, provided are also chelates, non-covalentcomplexes, and mixtures thereof, of the compounds described herein or apharmaceutically acceptable salt, tautomer, stereoisomer, mixture ofstereoisomers, prodrug, or deuterated analog thereof. A “chelate” isformed by the coordination of a compound to a metal ion at two (or more)points. A “non-covalent complex” is formed by the interaction of acompound and another molecule wherein a covalent bond is not formedbetween the compound and the molecule. For example, complexation canoccur through van der Waals interactions, hydrogen bonding, andelectrostatic interactions (also called ionic bonding).

Some of the compounds exist as tautomers. Tautomers are in equilibriumwith one another. For example, amide containing compounds may exist inequilibrium with imidic acid tautomers. Regardless of which tautomer isshown, and regardless of the nature of the equilibrium among tautomers,the compounds are understood by one of ordinary skill in the art tocomprise both amide and imidic acid tautomers. Thus, the amidecontaining compounds are understood to include their imidic acidtautomers. Likewise, the imidic acid containing compounds are understoodto include their amide tautomers.

Any formula or structure given herein is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated.Such isotopically labeled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The disclosure also includes “deuterated analogs” of compounds ofFormula I in which from 1 to n hydrogens attached to a carbon atomis/are replaced by deuterium, in which n is the number of hydrogens inthe molecule. Such compounds exhibit increased resistance to metabolismand are thus useful for increasing the half-life of any compound ofFormula I when administered to a mammal, particularly a human. See, forexample, Foster, “Deuterium Isotope Effects in Studies of DrugMetabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compoundsare synthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labeled or substituted therapeutic compounds of the disclosuremay have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies. Isotopically labeled compounds of thisdisclosure and prodrugs thereof can generally be prepared by carryingout the procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. Itis understood that deuterium in this context is regarded as asubstituent in the compound of Formula I.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

Therapeutic Uses of the Compounds

The compounds of the formulae described herein or a pharmaceuticallyacceptable salt, isomer, prodrug, or solvate thereof may be used for thetreatment of diseases and/or conditions mediated by PI3K isoforms. Inaddition, the application provides the compounds for use in therapy.Also, provided herein are methods for inhibiting one or more PI3Kisoforms. In one embodiment, provided are methods for inhibiting PI3Kβactivity using the compound described herein or a pharmaceuticallyacceptable salt, isomer, prodrug, or solvate thereof. In otherembodiment, provided are methods for inhibiting PI3Kβ activity using thecompound or a pharmaceutically acceptable salt, isomer, prodrug, orsolvate thereof. The application further provides methods for use insuch methods. The PI3K isoforms may be selectively or specificallyinhibited. Additionally, the compounds may be used to inhibit PI3Kactivity therapeutically or prophylactically, such as PI3Kβ.

The compounds according to the present application may be used incombination with one or more additional therapeutic agents. Thetherapeutic agents may be in the forms of compounds, antibodies,polypeptides, or polynucleotides. The therapeutic agent includes, but isnot limited to, a chemotherapeutic agent, an immunotherapeutic agent, aradiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent,an anti-proliferation agent, an anti-fibrotic agent, an anti-angiogenicagent, a therapeutic antibody, or any combination thereof. In oneembodiment, the application provides a product comprising a compounddescribed herein and an additional therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use in therapy,e.g. a method of treating a disease, disorder, or condition that ismediated by PI3K isoforms. The compounds of the invention can be used incombination with compounds that inhibit or modulate the activities ofpoly(ADP-ribose) polymerases (PARP), such as PARP-1, PARP-2, PARP-3 andVault-PARP; Tankyrases (TANKs), such as, TANK-1, TANK-2 and TANK-3;matrix metalloproteinases such as MMP-2 and MMP-9; and the androgenreceptor.

Therapeutic agents that can be used in combination with compounds of theinvention include enzalutamide, abiraterone, abiraterone acetate,apalutamide, galeterone, olaparib, niraparib, veliparib, rucaparib,flutamide, nilutamide, bicalutamide, ketonazole, orteronel, finasteride,dutasteride, bexlosteride, izonsteride, turosteride, episteride,dexamethasone, prednisone, leuprolide, goserelin, triptorelin,histrelin, estrogen, cyproterone acetate, spironolactone, flutamide,hydroxyflutamide, docetaxel, cabazitaxel, sipuleucel-T, ODM-201, VT-464,EPI-506, and combinations thereof.

Also, the therapeutic agents may be those that inhibit or modulate theactivities of Bruton's tyrosine kinase, spleen tyrosine kinase,apoptosis signal-regulating kinase, Janus kinase, lysyl oxidase, lysyloxidase-like proteins, matrix metallopeptidase, bromodomain-containingprotein, adenosine A2B receptor, isocitrate dehydrogenase,serine/threonine kinase TPL2, discoidin domain receptor,serine/threonine-protein kinases, IKK, MEK, EGFR, histone deacetylase,protein kinase C, or any combination thereof. In certain embodiments,the therapeutic agent may be selected from a PI3K (including PI3Kγ,PI3Kδ, PI3Kβ, PI3Kα, and/or pan-PI3K) inhibitor, a JAK (Janus kinase,including JAK1, JAK2, and/or JAK3) inhibitor, a SYK (spleen tyrosinekinase) inhibitor, a BTK (Bruton's tyrosine kinase) inhibitor, an A2B(adenosine A2B receptor) inhibitor, an ACK (activated CDC kinase,including ACK1) inhibitor, an ASK (apoptosis signal-regulating kinase,including ASK1) inhibitor, Aurora kinase, a BRD (bromodomain-containingprotein, including BRD4) inhibitor, a Bcl (B-cell CLL/lymphoma,including Bcl-1 and/or Bcl-2) inhibitor, a CAK (CDK-activating kinase)inhibitor, a CaMK (calmodulin-dependent protein kinases) inhibitor, aCDK (cyclin-dependent kinases, including CDK1, 2, 3, 4, and/or 6)inhibitor, a CK (casein kinase, including CK1 and/or CK2) inhibitor, aDDR (discoidin domain receptor, including DDR1 and/or DDR2) inhibitor, aEGFR inhibitor, a FXR (farnesoid×receptor) inhibitor, a FAK (focaladhesion kinase) inhibitor, a GSK (glycogen synthase kinase) inhibitor,a HDAC (histone deacetylase) inhibitor, an IDO (indoleamine2,3-dioxygenase) inhibitor, an IDH (isocitrate dehydrogenase, includingIDH1) inhibitor, an IKK (1-Kappa-B kinase) inhibitor, a KDM5 (lysinedemethylase) inhibitor, a LCK (lymphocyte-specific protein tyrosinekinase) inhibitor, a LOX (lysyl oxidase) inhibitor, a LOXL (lysyloxidase like protein, including LOXL1, LOXL2, LOXL3, LOXL4, and/orLOXL5) inhibitor, a MTH (mut T homolog) inhibitor, a MEK(mitogen-activated protein kinase kinase) inhibitor, a matrixmetalloprotease (MMP, including MMP2 and/or MMP9) inhibitor, amitogen-activated protein kinases (MAPK) inhibitor, a PD-1 (programmedcell death protein 1) inhibitor, a PD-L (programmed death-ligand 1)inhibitor, a PDGF (platelet-derived growth factor) inhibitor, aphosphorylase kinase (PK) inhibitor, a PLK (polo-like kinase, includingPLK1, 2, 3) inhibitor, a protein kinase (PK, including protein kinase A,B, C) inhibitor, a STK (serine/threonine kinase) inhibitor, a STAT(signal transduction and transcription) inhibitor, aserine/threonine-protein kinase inhibitor, a TBK (tank-binding kinase)inhibitor, a TLR (toll-like receptor modulators, including TLR-1, TLR-2,TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, TLR-12,and/or TLR-13) inhibitor, a TK (tyrosine kinase) inhibitor, a TPL2(serine/threonine kinase) inhibitor, a NEK9 inhibitor, an Abl inhibitor,a p38 kinase inhibitor, a PYK inhibitor, a PYK inhibitor, a c-Kitinhibitor, a NPM-ALK inhibitor, a Flt-3 inhibitor, a c-Met inhibitor, aKDR inhibitor, a TIE-2 inhibitor, a VEGFR inhibitor, a SRC inhibitor, aHCK inhibitor, a LYN inhibitor, a FYN inhibitor, a YES inhibitor, achemotherapeutic agent, an immunotherapeutic agent, a radiotherapeuticagent, an anti-neoplastic agent, an anti-cancer agent, ananti-proliferation agent, an anti-fibrotic agent, an anti-angiogenicagent, a therapeutic antibody, or any combination thereof. In someembodiments, the JAK inhibitor isN-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide asnamed by ChemDraw (may also be referred to as CYT0387 or momelotinib)and may be synthesized by the methods described in U.S. Pat. No.8,486,941. In certain embodiment, the SyK inhibitor is6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amineas named by ChemDraw (may also be referred to as6-(1H-indazol-6-yl)-N-[4-(morpholin-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-amine)and may be synthesized by the methods described in U.S. Pat. No.8,450,321. In other embodiments, the BTK inhibitor is(S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-oneas named by ChemDraw (may also be6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one)and may be synthesized by the methods in U.S. Pat. No. 8,557,803.

Chemotherapeutic agents may be categorized by their mechanism of actioninto, for example, the following groups: anti-metabolites/anti-canceragents, such as pyrimidine analogs (floxuridine, capecitabine, andcytarabine); purine analogs, folate antagonists and related inhibitors,antiproliferative/antimitotic agents including natural products such asvinca alkaloid (vinblastine, vincristine) and microtubule such as taxane(paclitaxel, docetaxel), vinblastin, nocodazole, epothilones andnavelbine, epidipodophyllotoxins (etoposide, teniposide); DNA damagingagents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil,cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin,doxorubicin, epirubicin, iphosphamide, melphalan, merchlorehtamine,mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere,teniposide, etoposide, triethylenethiophosphoramide); antibiotics suchas dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin),idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin; enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents;antiproliferative/antimitotic alkylating agents such as nitrogenmustards cyclophosphamide and analogs, melphalan, chlorambucil), and(hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) andanalogs, streptozocin), trazenes-dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate); platinum coordination complexes (cisplatin,oxiloplatinim, carboplatin), procarbazine, hydroxyurea, mitotane,aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen,goserelin, bicalutamide, nilutamide) and aromatase inhibitors(letrozole, anastrozole); anticoagulants (heparin, synthetic heparinsalts and other inhibitors of thrombin); fibrinolytic agents (such astissue plasminogen activator, streptokinase and urokinase), aspirin,dipyridamole, ticlopidine, clopidogrel; antimigratory agents;antisecretory agents (breveldin); immunosuppressives (tacrolimus,sirolimus azathioprine, mycophenolate); phytoestrogens (daidzein,glycitein, genisteinand growth factor inhibitors (vascular endothelialgrowth factor inhibitors, fibroblast growth factor inhibitors);angiotensin receptor blocker, nitric oxide donors; anti-senseoligonucleotides; antibodies (trastuzumab, rituximab); cell cycleinhibitors and differentiation inducers (tretinoin); inhibitors,topoisomerase inhibitors (doxorubicin (adriamycin), daunorubicin,dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecanand mitoxantrone, topotecan, irinotecan, camptothesin), corticosteroids(cortisone, dexamethasone, hydrocortisone, methylprednisolone,prednisone, and prednisolone); growth factor signal transduction kinaseinhibitors; dysfunction inducers, toxins such as Cholera toxin, ricin,Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, ordiphtheria toxin, and caspase activators; and chromatin.

As used herein the term “chemotherapeutic agent” or “chemotherapeutic”(or “chemotherapy,” in the case of treatment with a chemotherapeuticagent) is meant to encompass any non-proteinaceous (i.e, non-peptidic)chemical compound useful in the treatment of cancer. Examples ofchemotherapeutic agents include alkylating agents such as thiotepa andcyclophosphamide (CYTOXAN); alkyl sulfonates such as busulfan,improsulfan and piposulfan; aziridines such as benzodopa, carboquone,meturedopa, and uredopa; emylerumines and memylamelamines includingalfretamine, triemylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimemylolomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (includingsynthetic analogue topotecan); bryostatin; callystatin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); cryptophycins (articularly cryptophycin 1 and cryptophycin8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin;spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, foremustine, lomustine, nimustine,ranimustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gammaII and calicheamicin phiI1,see, e.g., Agnew, Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin,including dynemicin A; bisphosphonates, such as clodronate; anesperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromomophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, carrninomycin, carzinophilin, chromomycins, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin(including morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as demopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogues such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replinisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine;maytansinoids such as maytansine and ansamitocins; mitoguazone;mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid;2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-tricUorotriemylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethane; vindesine;dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta; taxoids,e.g., paclitaxel (TAXOL® and docetaxel (TAXOTERE®); chlorambucil;gemcitabine (Gemzar®); 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine;platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine;vinorelbine (Navelbine®); novantrone; teniposide; edatrexate;daunomycin; aminopterin; xeoloda; ibandronate; CPT-11; topoisomeraseinhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such asretinoic acid; capecitabine; FOLFIRI (fluorouracil, leucovorin, andirinotecan) and pharmaceutically acceptable salts, acids or derivativesof any of the above. One or more chemotherapeutic agent are used orincluded in the present application.

Also included in the definition of “chemotherapeutic agent” areanti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including Nolvadex™),raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene,LY117018, onapristone, and toremifene (Fareston®); inhibitors of theenzyme aromatase, which regulates estrogen production in the adrenalglands, such as, for example, 4(5)-imidazoles, aminoglutethimide,megestrol acetate (Megace®), exemestane, formestane, fadrozole, vorozole(Rivisor®), letrozole (Femara®), and anastrozole (Arimidex®); andanti-androgens such as flutamide, nilutamide, bicalutamide, leuprohde,and goserelin; and pharmaceutically acceptable salts, acids orderivatives of any of the above.

The anti-angiogenic agents include, but are not limited to, retinoidacid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN®,ENDOSTATIN®, suramin, squalamine, tissue inhibitor ofmetalloproteinase-1, tissue inhibitor of metalloproternase-2,plasminogen activator inhibitor-1, plasminogen activator inhibitor-2,cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), plateletfactor 4, protamine sulphate (clupeine), sulphated chitin derivatives(prepared from queen crab shells), sulphated polysaccharidepeptidoglycan complex (sp-pg), staurosporine, modulators of matrixmetabolism, including for example, proline analogs((1-azetidine-2-carboxylic acid (LACA), cishydroxyproline,d,I-3,4-dehydroproline, thiaproline, .alpha.-dipyridyl,beta-aminopropionitrile fumarate,4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate, mitoxantrone,heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin,beta-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodiumthiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum,alpba-2-antiplasmin, bisantrene, lobenzarit disodium,n-2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”,thalidomide; angiostatic steroid, cargboxynaminolmidazole;metalloproteinase inhibitors such as BB94. Other anti-angiogenesisagents include antibodies, preferably monoclonal antibodies againstthese angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGFisoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. See Ferrara N. and Alitalo, K.“Clinical application of angiogenic growth factors and their inhibitors”(1999) Nature Medicine 5:1359-1364.

The anti-fibrotic agents include, but are not limited to, the compoundssuch as beta-aminoproprionitrile (BAPN), as well as the compoundsdisclosed in U.S. Pat. No. 4,965,288 to Palfreyman, et al., issued Oct.23, 1990, entitled “Inhibitors of lysyl oxidase,” relating to inhibitorsof lysyl oxidase and their use in the treatment of diseases andconditions associated with the abnormal deposition of collagen; U.S.Pat. No. 4,997,854 to Kagan, et al., issued Mar. 5, 1991, entitled“Anti-fibrotic agents and methods for inhibiting the activity of lysyloxidase in situ using adjacently positioned diamine analogue substrate,”relating to compounds which inhibit LOX for the treatment of variouspathological fibrotic states, which are herein incorporated byreference. Further exemplary inhibitors are described in U.S. Pat. No.4,943,593 to Palfreyman, et al., issued Jul. 24, 1990, entitled“Inhibitors of lysyl oxidase,” relating to compounds such as2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; as well as, e.g.,U.S. Pat. Nos. 5,021,456; 5,5059,714; 5,120,764; 5,182,297; 5,252,608(relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine); and U.S. PatentApplication No. 2004/0248871, which are herein incorporated byreference. Exemplary anti-fibrotic agents also include the primaryamines reacting with the carbonyl group of the active site of the lysyloxidases, and more particularly those which produce, after binding withthe carbonyl, a product stabilized by resonance, such as the followingprimary amines: emylenemamine, hydrazine, phenylhydrazine, and theirderivatives, semicarbazide, and urea derivatives, aminonitriles, such asbeta-aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated orsaturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine,2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamines,selenohomocysteine lactone. Also, the anti-fibrotic agents are copperchelating agents, penetrating or not penetrating the cells. Exemplarycompounds include indirect inhibitors such compounds blocking thealdehyde derivatives originating from the oxidative deamination of thelysyl and hydroxylysyl residues by the lysyl oxidases, such as thethiolamines, in particular D-penicillamine, or its analogues such as2-amino-5-mercapto-5-methylhexanoic acid,D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid,p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid,sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate,2-acetamidoethyl-2-acetamidoethanethiol sulphanate,sodium-4-mercaptobutanesulphinate trihydrate.

The immunotherapeutic agents include and are not limited to therapeuticantibodies suitable for treating patients; such as abagovomab,adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab,anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab,bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab,cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab,daratumumab, drozitumab, duligotumab, dusigitumab, detumomab,dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab,ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab, figitumumab,flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab,glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab,inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab,lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab,matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab,narnatumab, naptumomab, necitumumab, nimotuzumab, nofetumomabn,ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab,oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab,pertuzumab, pintumomab, pritumumab, racotumomab, radretumab,rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab,siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumomab,tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab,tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab,zalutumumab, obinutuzumab, CC49 and 3F8. The exemplified therapeuticantibodies may be further labeled or combined with a radioisotopeparticle, such as indium In 111, yttrium Y 90, iodine I-131.

The application also provides method for treating a subject who isundergoing one or more standard therapies, such as chemotherapy,radiotherapy, immunotherapy, surgery, or combination thereof.Accordingly, one or more therapeutic agent or inhibitors may beadministered before, during, or after administration of chemotherapy,radiotherapy, immunotherapy, surgery or combination thereof.

Other examples of chemotherapy treatments (including standard orexperimental chemotherapies) are described below. In addition, treatmentof certain lymphomas is reviewed in Cheson, B. D., Leonard, J. P.,“Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma” The NewEngland Journal of Medicine 2008, 359(6), p. 613-626; and Wierda, W. G.,“Current and Investigational Therapies for Patients with CLL” Hematology2006, p. 285-294. Lymphoma incidence patterns in the United States areprofiled in Morton, L. M., et al. “Lymphoma Incidence Patterns by WHOSubtype in the United States, 1992-2001” Blood 2006, 107(1), p. 265-276.

Examples of immunotherapeutic agents include, but are not limited to,rituximab (such as Rituxan), alemtuzumab (such as Campath, MabCampath),anti-CD19 antibodies, anti-CD20 antibodies, anti-MN-14 antibodies,anti-TRAIL, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibodies,apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2-anti-CD22humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab,milatuzumab, ofatumumab, PRO 131921, SGN-40, WT-1 analog peptidevaccine, WT1 126-134 peptide vaccine, tositumomab, autologous humantumor-derived HSPPC-96, and veltuzumab. Additional immunotherapy agentsincludes using cancer vaccines based upon the genetic makeup of anindividual patient's tumor, such as lymphoma vaccine example is GTOP-99(MyVax®).

Examples of chemotherapy agents include aldesleukin, alvocidib,antineoplaston AS2-1, antineoplaston A10, anti-thymocyte globulin,amifostine trihydrate, aminocamptothecin, arsenic trioxide, betaalethine, Bcl-2 family protein inhibitor ABT-263, ABT-199, BMS-345541,bortezomib (Velcade®), bryostatin 1, busulfan, carboplatin, campath-1H,CC-5103, carmustine, caspofungin acetate, clofarabine, cisplatin,Cladribine (Leustarin), Chlorambucil (Leukeran), Curcumin, cyclosporine,Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), cytarabine,denileukin diftitox, dexamethasone, DT PACE, docetaxel, dolastatin 10,Doxorubicin (Adriamycin®, Adriblastine), doxorubicin hydrochloride,enzastaurin, epoetin alfa, etoposide, Everolimus (RAD001), fenretinide,filgrastim, melphalan, mesna, Flavopiridol, Fludarabine (Fludara),Geldanamycin (17-AAG), ifosfamide, irinotecan hydrochloride,ixabepilone, Lenalidomide (Revlimid®, CC-5013), lymphokine-activatedkiller cells, melphalan, methotrexate, mitoxantrone hydrochloride,motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen(Genasense) Obatoclax (GX15-070), oblimersen, octreotide acetate,omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylatedliposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin (Nipent),perifosine, Prednisolone, Prednisone, R-roscovitine (Selicilib, CYC202),recombinant interferon alfa, recombinant interleukin-12, recombinantinterleukin-11, recombinant flt3 ligand, recombinant humanthrombopoietin, rituximab, sargramostim, sildenafil citrate,simvastatin, sirolimus, Styryl sulphones, tacrolimus, tanespimycin,Temsirolimus (CCl-779), Thalidomide, therapeutic allogeneic lymphocytes,thiotepa, tipifarnib, Velcade® (bortezomib or PS-341), Vincristine(Oncovin), vincristine sulfate, vinorelbine ditartrate, Vorinostat(SAHA), vorinostat, and FR (fludarabine, rituximab), CHOP(cyclophosphamide, doxorubicin, vincristine, prednisone), CVP(cyclophosphamide, vincristine and prednisone), FCM (fludarabine,cyclophosphamide, mitoxantrone), FCR (fludarabine, cyclophosphamide,rituximab), hypezCVAD (hyperfractionated cyclophosphamide, vincristine,doxorubicin, dexamethasone, methotrexate, cytarabine), ICE(iphosphamide, carboplatin and etoposide), MCP (mitoxantrone,chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), R-CVP(rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE),and R-MCP (R-MCP).

The therapeutic treatments can be supplemented or combined with any ofthe abovementioned therapies with stem cell transplantation ortreatment. One example of modified approach is radioimmunotherapy,wherein a monoclonal antibody is combined with a radioisotope particle,such as indium In 111, yttrium Y 90, iodine I-131. Examples ofcombination therapies include, but are not limited to, Iodine-131tositumomab (Bexxar®), Yttrium-90 ibritumomab tiuxetan (Zevalin®),Bexxar® with CHOP.

Other therapeutic procedures include peripheral blood stem celltransplantation, autologous hematopoietic stem cell transplantation,autologous bone marrow transplantation, antibody therapy, biologicaltherapy, enzyme inhibitor therapy, total body irradiation, infusion ofstem cells, bone marrow ablation with stem cell support, invitro-treated peripheral blood stem cell transplantation, umbilical cordblood transplantation, immunoenzyme technique, pharmacological study,low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery,radiation therapy, and nonmyeloablative allogeneic hematopoietic stemcell transplantation.

In some embodiments, the methods include administering a compound of theformula described herein or a pharmaceutically acceptable salt, isomer,prodrug, or solvate thereof, in a therapeutically effective amount to ahuman in need thereof. The method can be employed to treat a patient whohas or is believed to have a disease or condition whose symptoms orpathology is mediated by expression or activity of PI3Kβ. The patientmay be a mammal or a human. In certain embodiment, the patient may be ahuman.

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing theeffect of another medication, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival.

“Prevention” or “preventing” mean any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” or “patient” refer to an animal, such as a mammal (including ahuman), that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human. “Human in needthereof” refers to a human who may have or is suspect to have diseases,or disorders, or conditions that would benefit from certain treatment;for example, being treated with the PI3K inhibitor of the compoundsaccording to the present application. In certain embodiments, thesubject may be a human who (i) has not received any treatment includingchemotherapy treatment, (ii) is substantially refractory to at least onechemotherapy treatment, (iii) is in relapse after treatment withchemotherapy, or both (i) and (ii). In some of embodiments, the subjectis refractory to at least one, at least two, at least three, or at leastfour chemotherapy treatments (including standard or experimentalchemotherapies).

The terms “therapeutically effective amount” or “effective amount” of acompound of the present application or a pharmaceutically acceptablesalt, isomers, prodrug, or solvate thereof, mean an amount sufficient toeffect treatment when administered to a subject, to provide atherapeutic benefit such as amelioration of symptoms or slowing ofdisease progression. For example, a therapeutically effective amount maybe an amount sufficient to decrease a symptom of a disease or conditionresponsive to inhibition of PI3Kδ and PI3Kβ activity. Thetherapeutically effective amount may vary depending on the subject, anddisease or condition being treated, the weight and age of the subject,the severity of the disease or condition, and the manner ofadministering, which can readily be determined by one or ordinary skillin the art.

In addition to the therapeutic uses, the compounds described herein havethe selectivity or selective inhibition to certain PI3K isoforms. In oneembodiment, the compounds have selectivity to PI3Kβ. The selectivity toPI3K isoforms may be determined by measuring the compound's activity ininhibiting certain PI3K isoforms using the assay described in theexample below or the methods commonly used. It is understood that theconditions (e.g. the reagent concentration or the incubationtemperature) may be varied and the results of the assay may vary. Insome instances, the value may vary within a range of one to three-fold.

The term “inhibition” indicates a decrease in the baseline activity of abiological activity or process. The term “inhibition of activity of PI3Kisoforms” or variants thereof refer to a decrease in activity in anyPI3K isoform (e.g., alpha, beta, gamma, or delta) as a direct orindirect response to the presence of a compound of any of the formuladescribed herein relative to the activity of PI3K isoform in the absenceof such compound. “Inhibition of PI3Kδ and/or PI3Kβ activities” orvariants thereof refer to a decrease in PI3Kδ and/or PI3Kβ activities asa direct or indirect response to the presence of the compounds describedherein, relative to the activities of PI3Kδ and/or PI3Kβ in the absenceof such compound. In some embodiments, the inhibition of PI3K isoformactivities may be compared in the same subject prior to treatment, orother subjects not receiving the treatment.

Without being bound to any theory, the decrease in the activity of PI3Kmay be due to the direct interaction of the compound with PI3K, or dueto the interaction of the compounds described herein with one or moreother factors that affect PI3K activity. For example, the presence ofthe compounds may decrease the activities of PI3Kδ and/or PI3Kβ bydirectly binding to PI3Kδ and/or PI3Kβ, by causing (directly orindirectly) another factor to decrease PI3Kδ and/or PI3Kβ activities, orby (directly or indirectly) decreasing the amount of PI3Kδ and/or PI3Kβpresent in the cell or organism.

The term “PI3K inhibitor” or variant thereof refers to a compound thatinhibits the activity of PI3K. The term “PI3K isoform selectiveinhibitor” or variant thereof refers to a compound that inhibits theactivity of one or more PI3K isoforms more effectively than the otherremaining PI3K isoforms. By way of example, the term “PI3Kβ selectiveinhibitor” generally refers to a compound that inhibits the activity ofthe PI3Kβ isoform more effectively than other isoforms of the PI3Kfamily, and the term “PI3Kδ selective inhibitor” generally refers to acompound that inhibits the activity of the PI3Kδ isoform moreeffectively than other isoforms of the PI3K family. The term “dualPI3Kδ/β selective inhibitor” generally refers to a compound thatinhibits the activity of both PI3Kδ and PI3Kβ isoforms more effectivelythan other isoforms of the PI3K family (e.g., PI3K α or γ).

The relative efficacies of compounds as inhibitors of an enzyme activity(or other biological activity) can be established by determining theconcentrations at which each compound inhibits the activity to apredefined extent and then comparing the results. In one embodiment, theefficacy of a compound as an inhibitor of one or more PI3K isoforms canbe measured by the compound concentration that inhibits 50% of theactivity in a biochemical assay, i.e., the 50% inhibitory concentrationor “IC₅₀”. The determination of IC₅₀ values can be accomplished usingconventional techniques known in the art, including the techniquesdescribed in the Examples below. In general, an IC₅₀ can be determinedby measuring the activity of a given enzyme in the presence of a rangeof concentrations of the compound under the study. The experimentallyobtained values of enzyme activity may then be plotted against thecompound concentrations used. The concentration of the inhibitor thatshows 50% enzyme activity (as compared to the activity in the absence ofany inhibitor) is taken as the IC₅₀ value. Analogously, other inhibitoryconcentrations can be defined through appropriate determinations ofactivity. For example, in some settings it may be desirable to establisha 90% inhibitory concentration, i.e., IC₉₀.

According to the present application, a PI3Kβ selective inhibitor is acompound that exhibits a 50% inhibitory concentration (IC₅₀) withrespect to PI3Kβ that is at least 10-fold, at least 20-fold, at least30-fold, at least 50-fold, at least 100-fold, at least 200-fold, or atleast 500-fold lower than the IC₅₀ with respect to either PI3Kα or PI3Kγor both PI3Kα and PI3Kγ. In addition, a PI3Kδ/β selective inhibitor is acompound that exhibits a 50% inhibitory concentration (IC₅₀) withrespect to PI3Kβ and PI3Kδ that is at least 10-fold, at least 20-fold,at least 30-fold, at least 50-fold, at least 75-fold, at least 100-fold,at least 200-fold, and at least 500-fold lower than the IC₅₀ withrespect to either PI3Kα or PI3Kγ. The dual PI3Kδ/β selective inhibitormay have the same or similar IC₅₀ to both PI3Kδ and PI3Kβ or may havedifferent IC₅₀ to either PI3Kδ or PI3Kβ. As used herein, the term“potency,” “potent,” or variants thereof refer to the compoundexhibiting an IC₅₀ value that is less than 100 nM. When comparing twocompounds, the compound that exhibits a lower IC₅₀ value is referred toas a more potent inhibitor.

The compounds of the present application exhibit unexpected selectivityto PI3Kβ. As shown in the example, certain compounds in Table 1 exhibitlow IC₅₀ values (e.g. 1 to 100 nM) against PI3Kβ. Certain compounds inTable 1a also exhibited such selectivity to PI3K isoforms. Also, certaincompounds of formula (I) exhibited at least between 10-fold to 400-foldlower IC₅₀ values for PI3Kβ than PI3Kγ, suggesting the compounds exhibitmore selectivity to PI3Kβ compared to PI3Kγ (i.e., inhibits the activityof the PI3Kβ isoform more effectively than the PI3Kγ isoform as shown bythe PI3Kγ/PI3Kβ ratio).

The methods described herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods described herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. Exemplary tissue samples includetumors and biopsies thereof. In this context, the compounds may be usedfor a variety of purposes, including therapeutic and experimentalpurposes. For example, it may be used ex vivo to determine the optimalschedule and/or dosing of administration of a PI3K selective inhibitorfor a given indication, cell type, individual, and other parameters.Information gleaned from such use may be used for experimental purposesor in the clinic to set protocols for in vivo treatment. Other ex vivouses for which the compound described herein may be suited are describedbelow or will become apparent to those skilled in the art. The compoundsof the formula described herein or a pharmaceutically acceptable salt,prodrug, or solvate thereof, may be further characterized to examine thesafety or tolerance dosage in human or non-human subjects. Suchproperties may be examined using commonly known methods to those skilledin the art.

Compared to other PI3K isoforms, PI3Kβ is generally mis-regulated incertain cancer cells. Aberrant proliferation of cells often interfereswith normal tissue function, which may result in abnormal cellularresponse such as immunity, inflammation, and/or apoptosis. The selectiveinhibitors to PI3Kβ are useful in treating, inhibiting, or preventingaberrant proliferation of cancerous and/or hematopoietic cells andameliorating the symptoms and secondary conditions.

The compounds described herein may be used to treat subjects havingvarious disease states, disorders, and conditions (also collectivelyreferred to as “indications”) associated with PI3K isoforms or theiractivities. As used herein, the terms “diseases,” “disorders,”“conditions” are used interchangeably. Such indications may include, forexample, cancer, including hematologic malignancies (e.g. leukemias andlymphomas, myeloproliferative disorders, myelodysplastic syndromes,plasma cell neoplasms) and solid tumors, inflammation, fibrosis,allergic conditions (including hypersensitivity), cardiovasculardiseases, neurodegenerative diseases, renal disorders, viral infections,obesity, and autoimmune diseases.

In other embodiments, the compounds described herein may be used totreat cancers that are mediated by, dependent on, or associated withPI3K activity. In certain embodiments, the disease or condition is anautoimmune disease, an inflammatory disease, or a cancer. In someembodiments, the disease or condition is chosen from rheumatoidarthritis, osteoarthritis, atherosclerosis, psoriasis, systemic lupuserythematosus, multiple sclerosis, inflammatory bowel disease, asthma,chronic obstructive airways disease, pneumonitis, dermatitis, alopecia,nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis,primary biliary cirrhosis, sclerosing cholangitis, diabetes (includingtype I diabetes), acute rejection of transplanted organs, lymphomas,multiple myelomas, leukemias, neoplasms and solid tumors.

In other embodiments, the disease is a solid tumor. By way of examples,the solid tumor includes but is not limited to prostate cancer,pancreatic cancer, bladder cancer, colorectal cancer, breast cancer,renal cancer, hepatocellular cancer, lung cancer, ovarian cancer,cervical cancer, rectum cancer, liver cancer, kidney cancer, stomachcancer, skin cancer, gastric cancer, esophageal cancer, head and neckcancer, melanoma, neuroendocrine cancers, CNS cancers (e.g.,neuroblastoma), brain tumors (e.g., glioma, anaplasticoligodendroglioma, adult glioblastoma multiforme, and adult anaplasticastrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments,the solid tumor is non-small cell lung cancer, small-cell lung cancer,colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer,pancreatic cancer, prostate cancer, or breast cancer.

The present application also provides a method for treating a human inneed thereof, who has or is suspected of having a disease or conditionresponsive or believed to be responsive to the inhibition PI3Kβ activityby administering to the subject a compound of the formulae describedherein or a pharmaceutically acceptable salt, enantiomer, atropisomer,tautomer, prodrug, or solvate thereof.

Additionally, the application provides a method of inhibiting kinaseactivity of a PI3Kβ polypeptides by contacting the polypeptides with acompound of the formulae described herein or a pharmaceuticallyacceptable salt, isomer, prodrug, solvate, or a mixture thereof.

Moreover, the application provides a method of decreasing cellviability, increasing cell death or apoptosis, increasing interferencewith PI3K signaling pathways (including AKT, S6RP, ERK phosphorylation),and/or reduction in chemokine production with an effective amount of acompound of any of the formulae described herein or a pharmaceuticallyacceptable salt, isomer, prodrug, solvate, or a mixture thereof.

The application further provides a method of disrupting leukocytefunction comprising contacting the leukocytes with an effective amountof a compound of any of the formulae described herein or apharmaceutically acceptable salt, isomer, prodrug, solvate, or a mixturethereof, in a human in need thereof.

Provided is also a method of inhibiting growth or proliferation ofcancer cells comprising contacting the cancer cells with an effectiveamount of a compound of the formulae described herein or apharmaceutically acceptable salt, isomer, prodrug, solvate, or a mixturethereof.

Kits

Provided herein are also kits that include a compound of the formulae ofthe present application or a pharmaceutically acceptable salt, isomer,prodrug, or solvate thereof, and suitable packaging. In one embodiment,a kit further includes instructions for use. In one aspect, a kitincludes a compound of the formulae described herein or apharmaceutically acceptable salt, isomer, prodrug, or solvate thereof,and a label and/or instructions for use of the compounds in thetreatment of the indications, including the diseases or conditions,described herein.

Provided herein are also articles of manufacture that include a compoundof any of the formulae described herein or a pharmaceutically acceptablesalt, isomer, prodrug, or solvate thereof, in a suitable container. Thecontainer may be a vial, jar, ampoule, preloaded syringe, andintravenous bag.

Pharmaceutical Compositions and Modes of Administration

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provides herein are alsopharmaceutical compositions that contain one or more of the compounds ofany of the formulae disclosed herein or a pharmaceutically acceptablesalt, isomers, prodrug, or solvate thereof, and one or morepharmaceutically acceptable vehicles selected from carriers, adjuvantsand excipients. Suitable pharmaceutically acceptable vehicles mayinclude, for example, inert solid diluents and fillers, diluents,including sterile aqueous solution and various organic solvents,permeation enhancers, solubilizers and adjuvants. Such compositions areprepared in a manner well known in the pharmaceutical art. See, e.g.,Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia,Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rdEd. (G. S. Banker & C. T. Rhodes, Eds.).

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical composition may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In certain embodiments, the pharmaceuticalcomposition may be administered by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant. In someembodiments, the pharmaceutical composition is administered orally.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds described herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound of any of the formulaedescribed herein or a pharmaceutically acceptable salt, prodrug, orsolvate thereof, the active ingredient is usually diluted by anexcipient and/or enclosed within such a carrier that can be in the formof a capsule, sachet, paper or other container. When the excipientserves as a diluent, it can be in the form of a solid, semi-solid, orliquid material, which acts as a vehicle, carrier or medium for theactive ingredient. Thus, the compositions can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, suspensions,emulsions, solutions, syrups, aerosols (as a solid or in a liquidmedium), ointments containing, for example, up to 10% by weight of theactive compound, soft and hard gelatin capsules, sterile injectablesolutions, and sterile packaged powders. In certain embodiments, thepharmaceutical composition is in the form of tablets.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions that include at least one compound of any of theformulae described herein or a pharmaceutically acceptable salt, isomer,prodrug, or solvate thereof, can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the subject by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds described herein in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may beconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of any of the above formulae or a pharmaceutically acceptablesalt, prodrug, or solvate thereof. When referring to thesepreformulation compositions as homogeneous, the active ingredient may bedispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation may include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect. In otherembodiments, compositions in pharmaceutically acceptable solvents may benebulized by use of inert gases. Nebulized solutions may be inhaleddirectly from the nebulizing device or the nebulizing device may beattached to a facemask tent, or intermittent positive pressure breathingmachine. Solution, suspension, or powder compositions may beadministered, preferably orally or nasally, from devices that deliverthe formulation in an appropriate manner.

Dosing

The specific dose level of a compound of the formulae described hereinfor any particular subject will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the subject undergoing therapy. Forexample, a dosage may be expressed as a number of milligrams of acompound of the formula per kilogram of the subject's body weight(mg/kg). Dosages of between about 0.01 and 200 mg/kg may be appropriate.In some embodiments, about 0.01 and 150 mg/kg may be appropriate. Inother embodiments a dosage of between 0.05 and 100 mg/kg may beappropriate. Normalizing according to the subject's body weight isparticularly useful when adjusting dosages between subjects of widelydisparate size, such as occurs when using the drug in both children andadult humans or when converting an effective dosage in a non-humansubject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compoundof the formulae administered per dose or per day. Daily dosage of acompound may be between about 1 mg and 2,000 mg, between about 1,000 to2,000 mg/day, between about 1 to 1,000 mg/day, between about 1 to 500mg/day, between about 100 to 150 mg/day, between about 1 to 100 mg/day,between about between about 1 to 50 mg/day, between about 50 to 100mg/day, between about 100 to 125 mg/day, between about 100 to 150mg/day, between about 100 to 175 mg/day, between about 100 to 200mg/day, between about 100 to 225 mg/day, between about 100 to 250mg/day, between about 100 to 350 mg/day, between about 100 to 400mg/day, between about 100 to 450 mg/day, or between about 100 to 500mg/day.

When administered orally, the total daily dosage for a human subject maybe between 1 mg and 1,000 mg/day, between about 1 to 100 mg/day, betweenabout 1 to 50 mg/day, between about 50 to 100 mg/day, between 50 to 300mg/day, between 50 to 200 mg/day, between 75 to 200 mg/day, between 75to 150 mg/day, between 100 to 200 mg/day, between about 200 to 300mg/day, between about 300 to 400 mg/day, between about 400 to 500mg/day, between about 100 to 150 mg/day, between about 150 to 200mg/day, between about 200 to 250 mg/day, between about 75 to 150 mg/day,or between about 150 to 300 mg/day.

The compounds of the present application or the compositions thereof maybe administered once, twice, three, or four times daily, using anysuitable mode described above. Also, administration or treatment withthe compounds according to any of the formulae described herein may becontinued for a number of days; for example, commonly treatment wouldcontinue for at least 7 days, 14 days, or 28 days, for one cycle oftreatment. In some treatment, the compound or the composition thereof isadministered continuously, i.e. every day. Treatment cycles are wellknown in cancer chemotherapy, and are frequently alternated with restingperiods of about 1 to 28 days, commonly about 7 days or about 14 days,between cycles. The treatment cycles, in other embodiments, may also becontinuous.

In a particular embodiment, the method comprises administering to thesubject an initial daily dose of about 1 to 500 mg of a compound of theabove formula and increasing the dose by increments until clinicalefficacy is achieved. Increments of about 1, 5, 10, 25, 50, 75, or 100mg can be used to increase the dose. The dosage can be increased daily,every other day, twice per week, or once per week.

Synthesis of the Compounds

The compounds of the present application may be prepared using themethods disclosed herein and routine modifications thereof, which willbe apparent given the disclosure herein and methods well known in theart. Conventional and well-known synthetic methods may be used inaddition to the teachings herein. The synthesis of typical compoundsdescribed herein may be accomplished as described in the followingexamples. If available, reagents may be purchased commercially, e.g.,from Sigma Aldrich or other chemical suppliers. In general, compoundsdescribed herein are typically stable and isolatable at room temperatureand pressure.

General Synthesis

Typical embodiments of compounds described herein may be synthesizedusing the general reaction schemes described below. It will be apparentgiven the description herein that the general schemes may be altered bysubstitution of the starting materials with other materials havingsimilar structures to result in products that are correspondinglydifferent. Descriptions of syntheses follow to provide numerous examplesof how the starting materials may vary to provide correspondingproducts. Given a desired product for which the substituent groups aredefined, the necessary starting materials generally may be determined byinspection. Starting materials are typically obtained from commercialsources or synthesized using published methods. For synthesizingcompounds which are embodiments described in the present disclosure,inspection of the structure of the compound to be synthesized willprovide the identity of each substituent group. The identity of thefinal product will generally render apparent the identity of thenecessary starting materials by a simple process of inspection, giventhe examples herein.

Synthetic Reaction Parameters

The terms “solvent”, “inert organic solvent”, or “inert solvent” referto a solvent inert under the conditions of the reaction being describedin conjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, and the like). Unless specified to the contrary, the solventsused in the reactions of the present invention are inert organicsolvents, and the reactions are carried out under an inert gas,preferably nitrogen or argon.

The compounds of formula (I) may be prepared using the method similar tothe Reaction Scheme I shown below:

Step 1—Preparation of a Compound of Formula (1) The compounds of formula1 can be prepared by treating an appropriately substituted haloquinoline(A, X=halide, preferably bromo or chloro) with an appropriatelysubstituted aniline in the presence of a palladium catalyst, such asPd(OAc)₂, a phosphine ligand, such asdicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine, and abase, such as potassium phosphate in a neutral solvent such as toluene.The reaction can be carried out between 30° C. and 120° C. for between 4and 72 hours or until the reaction is complete. Upon completion, thesolvent is removed in vacuo and the material can be purified by knownmethods such as chromatography, precipitation, or crystallization.Alternatively, compounds of formula 1 can be prepared by reacting anappropriately substituted aminoquinoline (X═NH₂) with an appropriatelysubstituted 2-halonitroaromatic compound in the presence of a base, suchas cesium carbonate or potassium carbonate, in a solvent, such as DMF orDMSO. The reaction is carried out between 30° C. and 120° C. for between4 and 72 hours or until the reaction is complete. Upon completion, thesolvent is removed in vacuo and the material may be purified by knownmethods such as chromatography, precipitation, or crystallization.

Step 2-Preparation of a Compound of Formula 2

The compounds of formula 2 can be made by treating the nitroaniline withthe appropriate aldehyde and a reducing agent, such as sodium dithionitein a solvent to assure dissolution of the nitro containing compound. Thereaction is carried out between 30° C. and 120° C. for between 4 and 72hours or until the reaction is complete and partitioned between waterand an organic solvent such as ethyl acetate or methylene chloride. Theorganic phase was separated and the solvent removed to leave a residue,which may be purified by known methods such as chromatography,precipitation or crystallization. The compounds of formula 2 may also bemade in two steps by first reducing the compound of formula 1 bystandard methods, with appropriate reagents such as tin chloride, ferricchloride, or hydrogen and a palladium or platinum catalyst. Theresulting ortho dianiline can be cyclized with the appropriate orthoester to give the benzimidazole, 2.

Step 3-Preparation of a Compound of Formula 3

The compounds of formula 3 may be prepared by deesterifying a compoundof formula 2, in which Y is CO₂Me by standard methods. A compound offormula 2 is dissolved or slurried in a solvent such as THF or dioxaneand LiOH may be added either as a solution in water or with some water.The reaction is carried out at ambient temperature for between 4 and 72hours or until the reaction is complete and acidified with an acid suchas HCl. The solvent is removed in vacuo to give a compound of formula 3.Alternatively, t-butyl esters (Y is CO₂t-butyl) can be converted to thecorresponding acid by treatment with an acid, such as TFA or aqueousHCl, in a solvent such as dichloromethane. The reaction is carried outbetween 0° C. and 60° C. for between 4 and 72 hours or until thereaction is complete at which time the solvent is removed in vacuo.

Step 4-Preparation of a Compound of Formula 4

The compound of formula 4 may be prepared by amidation of a compound offormula 3 by standard coupling conditions. For example, the acid, 3, maybe reacted with ammonium chloride in the presence of HOBT or HATU, abase such as triethylamine, diisopropylethylamine, or methylmorpholine,and diethyldiazodicarboxylate orN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride in a solvent such as DMF. The reaction is carried out atambient temperature for between 12 and 96 hours or until the reaction iscomplete. The amide may precipitate with the addition of water or can beisolated by standard extractive methods.

Step 5-Preparation of a Compound of Formula 5

Compounds of formula 5 may be prepared from a compound of formula 4 byfirst reacting a compound of formula 4 with the appropriate reagent suchas 1,1-dimethoxy-N,N-dimethylethanamine to prepare methyltriazoles or1,1-dimethoxy-N,N-dimethylmethanamine to make unsubstituted triazolesbetween 80° C. and 150° C. for between 0.5 and 5 hours or until thereaction is complete. Alternatively substituted triazoles may beprepared by using alternative reagents. The solvent is removed in vacuoand the residue is dissolved in acetic acid and hydrazine hydrate andstirred for between 80° C. and 150° C. for between 0.5 and 5 hours oruntil the reaction is complete. The solvent was removed in vacuo and theresidue was purified by standard methods. If protecting groups arepresent on the compound at this point, they may be removed byappropriate methods. For example, trityl or Boc groups may be removed bytreatment with an acid, such as HCl or trifluoroacetic acid in a solventsuch as methylene chloride. If the compound is a mixture ofatropisomers, the isomers may be separated using a chiral chromatographymethod. The solvents and chromatography column used will depend on thespecific compound being separated, but normal phase, reverse phase orsupercritical fluid chromatography may be used. Alternatively, acompound of formula 5 may be prepared by reacting a compound of formula2 with ammonium chloride and trimethylaluminum in a solvent such as DCEbetween −20° C. and 100° C. for between 3 hours and 3 days or until thereaction is complete. Work-up and purification gives the nitrile whichcan be further reacted with sodium azide and ammonium chloride in asolvent such as DMF between 80° C. and 150° C. for between 2 and 24hours or until the reaction is complete. Alternatively a compound offormula 5 may be prepared by reacting a compound of formula 2 whereY═CO₂Me with a diamine, such as ethylenediamine, in the presence oftrimethylaluminum in a solvent such as toluene between 10° C. and 150°C. for between 1 and 24 hours or until the reaction is complete.Alternatively a compound of formula 5 may be prepared by reacting acompound of formula 2 where Y═CO₂Me with hydrazine hydrate in anappropriate solvent such as ethanol between 40° C. and reflux forbetween 2 and 24 hours or until the reaction is complete. Work-up andpurification gives the hydrazide which can be further reacted with anorthoester, such as trimethylorthoformate, triethylorthoacetate, and thelike, to give an 1,3,4-oxadiazole, cyanogen bromide to give a2-amino-1,3,4-oxadiazole, carbon disulfide to give an1,3,4-oxadiazole-2-thione, trimethylisocyante to give an2-amino-1,3,4-thiadiazole, or phosgene or an equivalent, such ascarbonyldiimidazole to give an 1,3,4-oxadiazol-2(3H)-one.

Step 6-Preparation of a Compound of Formula 5

Compounds of formula 5 may also be prepared by reacting a compound offormula 2, Y is a halogen, preferably bromide, with an appropriatelysubstituted tributylstannyl substituted reagent in the presence ofcatalysts, such as copper iodide and palladium in a solvent, such asdioxane between 50° C. and 150° C. for between 12 hours and 7 days, oruntil the reaction is complete under an inert atmosphere such as Argon.The reaction may be worked up by standard means and purified by standardmethods, such as chromatography. Alternatively, a compound of formula 5may be prepared by reacting a compound of formula 2, where Y is ahalogen, preferably bromide, with an appropriately substituted boronicacid, a MIDA ester of a boronic acid, or pinacol ester of a boronic acidin the presence of cesium fluoride in the presence of catalysts, such ascopper iodide and palladium in a solvent, such as dioxane between 50° C.and 150° C. for between 12 hours and 7 days, or until the reaction iscomplete under an inert atmosphere such as Argon. The reaction may beworked up by standard means and purified by standard methods, such aschromatography. In some cases the product may have had a protectinggroup and deprotection would proceed by methods known to those skilledin the art. For example, a THP or Boc group would be removed bytreatment with an acid such as TFA or aqueous HCl. Alternatively acompound of formula 5 may be prepared by reacting a compound of formula2 (Y═Br) with ethynyltributylstannane in the presence of Pd(dppf)Cl₂ andcopper iodide in a solvent such as dioxane between 50° C. and 150° C.for between 12 hours and 7 days, or until the reaction is complete underan inert atmosphere such as Argon. The resulting acetylene containingcompound is subsequently reacted with azidotrimethylsilane in thepresence of a catalyst such as copper iodide or a solvent such as amixture of DMF and MeOH between 50° C. and 150° C. for between 8 and 24hours or until the reaction is complete to give a 1,2,3-triazole afterpurification by standard means.

Step 7-Preparation of a Compound of Formula 1a

Compounds of formula 1a may be prepared by methods similar to thatdescribed in step 6 from compounds of formula 1 (Y═Br).

Step 8-Preparation of Compounds of Formula 5

Compounds of formula 5 may be prepared by methods similar to thatdescribed in step 2.

EXAMPLES Step 1. Methyl3-((8-chloroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate

Palladium (II) acetate (0.14 g, 0.61 mmol) was added to a mixture ofmethyl 3-amino-5-morpholino-2-nitrobenzoate (1.50 g, 5.33 mmol),4,8-dichloroquinoline (1.16 g, 5.87 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.87g, 1.82 mmol), and potassium phosphate (3.22 g, 15.15 mmol) in toluene(10 mL). The resultant was degassed and stirred at 90° C. for 16 hours.The reaction mixture was cooled to room temperature and dry loaded ontosilica gel and purified eluting with 0 to 100% ethyl acetate in hexanesto afford the title compound as a brown solid. ES/MS m/z=443.30 (M+H)⁺.

The compounds listed below were prepared in a manner similar to thatdescribed in step 1 above using appropriate intermediates and chemistry:

-   methyl    3-((5,8-difluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((5-chloro-8-fluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-chloroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((7-fluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl 5-morpholino-2-nitro-3-(quinolin-4-ylamino)benzoate;-   methyl    3-((8-chloro-5-fluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-chloro-6-fluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-chloro-7-fluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((5-fluoro-8-methylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((7,8-difluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-fluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((2-cyclopropyl-3-methylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((2-ethyl-3-methylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    5-morpholino-2-nitro-3-((2-phenylquinolin-4-yl)amino)benzoate;-   methyl    3-((2-methyl-8-(trifluoromethyl)quinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((3-ethyl-2-methylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((7-fluoro-2-methylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-fluoro-2,3-dimethylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl 3-((2-cyanoquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((3-cyclopropylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((3-methylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-chloro-2-methylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((2-methylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-chloro-2,3-dimethylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-chloro-3-methylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((2-ethyl-8-fluoro-3-methylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((5-(difluoromethyl)quinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((5-chloroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((5-fluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((5-methylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-(difluoromethyl)quinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((7-fluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-chloro-2-(difluoromethyl)quinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-chloro-5-fluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl 3-((8-cyanoquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((5,8-dichloroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    5-morpholino-2-nitro-3-((2-(thiazol-4-yl)quinolin-4-yl)amino)benzoate;-   methyl    3-((3-chloroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((5,7-difluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((6,8-difluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((3,8-dichloroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((3-chloro-8-fluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-methylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    5-morpholino-2-nitro-3-((8-(trifluoromethyl)quinolin-4-yl)amino)benzoate;-   tert-butyl    3-((8-chloroquinolin-4-yl)amino)-4-fluoro-5-morpholino-2-nitrobenzoate;-   methyl    (S)-3-((8-chloroquinolin-4-yl)amino)-5-(3-methylmorpholino)-2-nitrobenzoate;-   methyl    (R)-3-((8-chloroquinolin-4-yl)amino)-5-(3-methylmorpholino)-2-nitrobenzoate;-   tert-butyl    3-((8-chloroquinolin-4-yl)amino)-6-fluoro-5-morpholino-2-nitrobenzoate;-   8-chloro-N-(5-morpholino-2-nitro-3-(pyridin-3-yl)phenyl)quinolin-4-amine;-   8-chloro-N-(5-morpholino-2-nitro-[1,1′-biphenyl]-3-yl)quinolin-4-amine;-   methyl    5-morpholino-2-nitro-3-((2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)amino)benzoate;-   tert-butyl    4-(4-((3-(methoxycarbonyl)-5-morpholino-2-nitrophenyl)amino)quinolin-2-yl)piperazine-1-carboxylate;-   methyl    3-((3-fluoroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-chloro-5-fluoroquinolin-4-yl)amino)-4-fluoro-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-chloroquinolin-4-yl)amino)-4-fluoro-5-morpholino-2-nitrobenzoate;-   methyl    3-((8-cyano-3-methylquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate;-   tert-butyl    4-(4-((3-(methoxycarbonyl)-5-morpholino-2-nitrophenyl)amino)quinolin-2-yl)piperazine-1-carboxylate;-   methyl    5-morpholino-2-nitro-3-((2-(1-trityl-1H-pyrazol-3-yl)quinolin-4-yl)amino)benzoate;-   methyl    5-morpholino-2-nitro-3-((2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)amino)benzoate;-   methyl 3-((3-cyanoquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate.

Step 1a: N-(3-bromo-5-morpholino-2-nitrophenyl)-8-fluoroquinolin-4-amine

4-amino-8-fluoroquinoline (500 mg, 3.1 mmol),4-(3-bromo-5-fluoro-4-nitrophenyl)morpholine (941 mg, 3.1 mmol), andcesium carbonate (2.2 g, 6.8 mmol) were combined in DMF (4 mL). Theresulting mixture was heated to 90° C. After 18 hours the reaction wasallowed to cool and poured into water. The resulting precipitate waswashed with water, then methanol, and dried to affordN-(3-bromo-5-morpholino-2-nitrophenyl)-8-fluoroquinolin-4-amine. ES/MSm/z 447.07.

The compounds listed below were prepared in a manner similar to thatdescribed above using appropriate intermediates:

-   N-(3-bromo-5-morpholino-2-nitrophenyl)-5,8-difluoroquinolin-4-amine;-   N-(3-bromo-5-morpholino-2-nitrophenyl)-8-chloroquinolin-4-amine;-   N-(3-bromo-5-morpholino-2-nitrophenyl)-8-fluoro-2-methylquinolin-4-amine;-   N-(3-bromo-5-morpholino-2-nitrophenyl)-8-chloro-6-fluoroquinolin-4-amine;-   N-(3-bromo-5-morpholino-2-nitrophenyl)-8-chloro-7-fluoroquinolin-4-amine;-   N-(3-bromo-5-morpholino-2-nitrophenyl)-8-chloro-5-fluoroquinolin-4-amine;-   N-(3-bromo-5-morpholino-2-nitrophenyl)-7-fluoroquinolin-4-amine;-   N-(3-bromo-5-morpholino-2-nitrophenyl)quinolin-4-amine;-   N-(3-bromo-5-morpholino-2-nitrophenyl)-5-chloro-8-fluoroquinolin-4-amine.

Step 2. Methyl1-(8-chloroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylate

Butyraldehyde (0.9 mL, 10.44 mmol) was added to a solution of methyl3-((8-chloroquinolin-4-yl)amino)-5-morpholino-2-nitrobenzoate (600 mg,1.36 mmol) and sodium dithionite (833 mg, 4.07 mmol) in ethanol (3 mL)and DMSO (3 mL). The reagents were stirred at 80° C. for 16 hours, afterwhich time the reaction mixture was cooled to ambient temperature andpartitioned between ethyl acetate (50 mL) and water (50 mL). The aqueouslayer was extracted 3 times with ethyl acetate. The combined organicphases were dried with sodium sulfate and filtered. The resultantresidue was purified on silica gel with 0 to 15% methanol in ethylacetate to afford the title compound as an orange solid. ES/MSm/z=465.235 (M+H)⁺.

The compounds listed below were prepared in a manner similar to thatdescribed above using appropriate intermediates:

-   methyl    1-(5,8-difluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5-chloro-8-fluoroquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-2-(1-methylcyclopropyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-2-isobutyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(7-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-2-(cyclopropylmethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-6-morpholino-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    6-morpholino-2-(pyridin-2-yl)-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-5-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-2-(1-methoxyethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-2-cyclobutyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-6-morpholino-2-(pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-2-isopropyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-6-morpholino-2-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-6-morpholino-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-cyclopropyl-6-morpholino-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(7-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-6-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-(tert-butyl)-1-(8-chloroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-methyl-6-morpholino-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    (S)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5,8-difluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-7-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    6-morpholino-2-(oxetan-3-yl)-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5-fluoro-8-methylquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-6-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-7-fluoroquinolin-4-yl)-2-(cyclopropylmethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-7-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-7-fluoroquinolin-4-yl)-2-cyclopropyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-7-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    6-morpholino-2-propyl-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5,8-difluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(7,8-difluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-2-cyclopropyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-fluoroquinolin-4-yl)-2-(2-methoxyethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(7,8-difluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(7-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-2-(1-fluorocyclopropyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(2-cyclopropyl-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(2-ethyl-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-2-(trifluoromethyl)quinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-methyl-6-morpholino-1-(2-phenylquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(3-ethyl-2-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(7-fluoro-2-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-fluoro-2,3-dimethylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-methyl-1-(2-methyl-8-(trifluoromethyl)quinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(2-cyanoquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(3-cyclopropylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-2-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-methyl-1-(3-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(2-ethyl-3-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(3-ethyl-2-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-2,3-dimethylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-methyl-1-(2-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(2-ethyl-8-fluoro-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5-(difluoromethyl)quinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5-chloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-(difluoromethyl)quinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-methyl-1-(5-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-2-(difluoromethyl)quinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-cyanoquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5,8-dichloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5,8-difluoroquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5,8-difluoroquinolin-4-yl)-6-morpholino-2-(oxetan-3-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5-chloro-8-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5-fluoro-8-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-methyl-6-morpholino-1-(2-(thiazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(3-chloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5,7-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(6,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(7,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-cyclopropyl-1-(7,8-difluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-cyclopropyl-1-(8-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-ethyl-1-(8-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(3,8-dichloroquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(3,8-dichloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(3-chloro-8-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5-chloro-8-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(6,8-difluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-2-cyclopropyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-ethyl-6-morpholino-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-methyl-1-(8-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-methyl-6-morpholino-1-(8-(trifluoromethyl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-methyl-6-morpholino-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-2-(2-methoxyethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-6-morpholino-2-(oxazol-5-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-6-morpholino-2-(pyridin-2-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-6-morpholino-2-(thiazol-5-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-6-morpholino-2-(oxetan-3-yl)-1H-benzo[d]imidazole-4-carboxylate;-   4-(4-bromo-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine    (ES/MS m/z 443.1);-   4-(4-bromo-1-(5,8-difluoroquinolin-4-yl)-2-ethyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-chloroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-fluoro-2-methylquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-2-ethyl-1-(8-fluoro-2-methylquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-2-ethyl-1-(8-fluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(5,8-difluoroquinolin-4-yl)-2-isobutyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-chloro-6-fluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-chloro-7-fluoroquinolin-4-yl)-2-ethyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-chloroquinolin-4-yl)-2-(cyclopropylmethyl)-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-2-(cyclopropylmethyl)-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-2-cyclopropyl-1-(8-fluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(5,8-difluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(5,8-difluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-chloroquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-chloroquinolin-4-yl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-chloroquinolin-4-yl)-2-ethyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-fluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-chloro-5-fluoroquinolin-4-yl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-2-cyclopropyl-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(7-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-chloro-6-fluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-chloroquinolin-4-yl)-2-(oxetan-3-yl)-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-fluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-2-(cyclopropylmethyl)-1-(8-fluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-2-methyl-1-(quinolin-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(5-chloro-8-fluoroquinolin-4-yl)-2-ethyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(5-chloro-8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-chloro-7-fluoroquinolin-4-yl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)morpholine;-   4-(4-bromo-1-(8-chloro-7-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine;-   tert-butyl    1-(8-chloroquinolin-4-yl)-7-fluoro-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    (S)-1-(8-chloroquinolin-4-yl)-2-methyl-6-(3-methylmorpholino)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    (R)-1-(8-chloroquinolin-4-yl)-2-methyl-6-(3-methylmorpholino)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-6-morpholino-2-(1H-pyrazol-5-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-2-(isothiazol-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-6-morpholino-2-(1H-pyrazol-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   tert-butyl    1-(8-chloroquinolin-4-yl)-5-fluoro-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    2-methyl-6-morpholino-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(3-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloro-5-fluoroquinolin-4-yl)-7-fluoro-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-chloroquinolin-4-yl)-7-fluoro-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-cyano-3-methylquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(8-cyano-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate-   methyl    1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    6-morpholino-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    6-morpholino-1-(2-(1-trityl-1H-pyrazol-3-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(3-cyanoquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;-   methyl    1-(3-cyanoquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate;

Step 3:1-(8-Chloroqulnolln-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylicacid

Aqueous lithium hydroxide (1M, 3.8 mL) was added to methyl1-(8-chloroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylate(443 mg, 0.95 mmol) in THF (2 mL). The reaction was stirred at ambienttemperature for 16 hours. The reaction mixture was acidified to pH 6with the addition of 6M HCl. The resultant solution was concentrated invacuuo to afford the title compound. ES/MS m/z 451.40 (M+H)⁺.

The compounds listed below were prepared in a manner similar to thatdescribed above using appropriate intermediates:

-   1-(5,8-difluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5-chloro-8-fluoroquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-2-(1-methylcyclopropyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-2-isobutyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(7-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-2-(cyclopropylmethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   6-morpholino-2-(pyridin-2-yl)-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-5-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-2-(1-methoxyethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-2-cyclobutyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-2-isopropyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-cyclopropyl-6-morpholino-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(7-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-6-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-(tert-butyl)-1-(8-chloroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-methyl-6-morpholino-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   (S)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5,8-difluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-7-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   6-morpholino-2-(oxetan-3-yl)-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5-fluoro-8-methylquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-6-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-7-fluoroquinolin-4-yl)-2-(cyclopropylmethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-7-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-7-fluoroquinolin-4-yl)-2-cyclopropyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-7-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   6-morpholino-2-propyl-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5,8-difluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(7,8-difluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-2-cyclopropyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-fluoroquinolin-4-yl)-2-(2-methoxyethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(7,8-difluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(7-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-2-(1-fluorocyclopropyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(2-cyclopropyl-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(2-ethyl-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-2-(trifluoromethyl)quinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-methyl-6-morpholino-1-(2-phenylquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(3-ethyl-2-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(7-fluoro-2-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-fluoro-2,3-dimethylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-methyl-1-(2-methyl-8-(trifluoromethyl)quinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(2-cyanoquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(3-cyclopropylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-2-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-methyl-1-(3-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(2-ethyl-3-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(3-ethyl-2-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-2,3-dimethylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-methyl-1-(2-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(2-ethyl-8-fluoro-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5-(difluoromethyl)quinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5-chloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-(difluoromethyl)quinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-methyl-1-(5-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-2-(difluoromethyl)quinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-cyanoquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5,8-dichloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5,8-difluoroquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5,8-difluoroquinolin-4-yl)-6-morpholino-2-(oxetan-3-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5-chloro-8-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5-fluoro-8-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-methyl-6-morpholino-1-(2-(thiazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(3-chloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5,7-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(6,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(7,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-cyclopropyl-1-(7,8-difluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-cyclopropyl-1-(8-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-ethyl-1-(8-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(3,8-dichloroquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(3,8-dichloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(3-chloro-8-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5-chloro-8-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(6,8-difluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-2-cyclopropyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-ethyl-6-morpholino-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-methyl-1-(8-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-methyl-6-morpholino-1-(8-(trifluoromethyl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-methyl-6-morpholino-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-2-(2-methoxyethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(oxazol-5-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(pyridin-2-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(thiazol-5-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(oxetan-3-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   (S)-1-(8-chloroquinolin-4-yl)-2-methyl-6-(3-methylmorpholino)-1H-benzo[d]imidazole-4-carboxylic    acid;-   (R)-1-(8-chloroquinolin-4-yl)-2-methyl-6-(3-methylmorpholino)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(1H-pyrazol-5-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-2-(isothiazol-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(1H-pyrazol-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   2-methyl-6-morpholino-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(3-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloro-5-fluoroquinolin-4-yl)-7-fluoro-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-chloroquinolin-4-yl)-7-fluoro-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-cyano-3-methylquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(8-cyano-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(3-carbamoylquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(3-carbamoylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid;-   6-morpholino-1-(2-(1-trityl-1H-pyrazol-3-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;-   6-morpholino-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxylic    acid;

Step 3a:1-(8-chloroquinolin-4-yl)-5-fluoro-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylicacid

To a solution of tert-butyl1-(8-chloroquinolin-4-yl)-5-fluoro-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate(170 mg, 0.34 mmol) in DCM (3.0 mL) was added TFA (0.4 mL). The mixturewas stirred at room temperature for 20 hours and concentrated in vacuuoto afford1-(8-chloroquinolin-4-yl)-5-fluoro-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylicacid which was used without further purification in the next step.

The following compound was prepared in a manner similar to thatdescribed above using appropriate intermediates:

-   1-(8-chloroquinolin-4-yl)-7-fluoro-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylic    acid.

Step:1-(8-Chloroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxamide

Hünig's base (1.35 mL, 7.74 mmol) was added to1-(8-chloroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxylicacid (349 mg, 0.77 mmol), ammonium hydrochloride (248 mg, 4.64 mmol),1H-benzo[d][1,2,3]triazol-1-ol hydrate (356 mg, 2.32 mmol), andN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (445 mg, 2.32 mmol) in DMF (3 mL). The reagents werestirred at ambient temperature for 72 hours. Material precipitated withthe addition of water. The resulting solid was filtered, washed withwater, and dried under high vacuum to afford the title compound as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.30 (d, 1H), 9.20 (d, 1H),8.10 (d, 1H), 7.98 (d, 1H), 7.89 (d, 1H), 7.65-7.55 (m, 2H), 7.20 (d,1H), 6.64 (d, 1H), 3.64 (t, J=4.7 Hz, 4H), 3.03-2.92 (m, 4H), 2.66-2.52(m, 2H), 1.72-1.58 (m, 2H), 0.82 (t, J=7.4, 0.6 Hz, 3H). ES/MS m/z450.20 (M+H)⁺.

The compounds listed below were prepared in a manner similar to thatdescribed above using appropriate intermediates and chemistry:

-   1-(5,8-difluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxamide;-   1-(5-chloro-8-fluoroquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-2-(1-methylcyclopropyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-2-isobutyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(7-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-2-(cyclopropylmethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole-4-carboxamide;-   6-morpholino-2-(pyridin-2-yl)-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-5-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-2-(1-methoxyethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-2-cyclobutyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-2-isopropyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(pyridin-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazole-4-carboxamide;-   2-cyclopropyl-6-morpholino-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(7-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-6-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   2-(tert-butyl)-1-(8-chloroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   2-methyl-6-morpholino-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   (S)-1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(5,8-difluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-7-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   6-morpholino-2-(oxetan-3-yl)-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(5-fluoro-8-methylquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-6-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-7-fluoroquinolin-4-yl)-2-(cyclopropylmethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-7-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-7-fluoroquinolin-4-yl)-2-cyclopropyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-7-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   6-morpholino-2-propyl-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(5,8-difluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(7,8-difluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-2-cyclopropyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-fluoroquinolin-4-yl)-2-(2-methoxyethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(7,8-difluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxamide;-   1-(7-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-2-(1-fluorocyclopropyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(2-cyclopropyl-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(2-ethyl-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-2-(trifluoromethyl)quinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   2-methyl-6-morpholino-1-(2-phenylquinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(3-ethyl-2-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(7-fluoro-2-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-fluoro-2,3-dimethylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   2-methyl-1-(2-methyl-8-(trifluoromethyl)quinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(2-cyanoquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(3-cyclopropylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-2-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   2-methyl-1-(3-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(2-ethyl-3-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(3-ethyl-2-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-2,3-dimethylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   2-methyl-1-(2-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(2-ethyl-8-fluoro-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(5-(difluoromethyl)quinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(5-chloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(5-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-(difluoromethyl)quinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   2-methyl-1-(5-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-2-(difluoromethyl)quinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-cyanoquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(5,8-dichloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(5,8-difluoroquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(5,8-difluoroquinolin-4-yl)-6-morpholino-2-(oxetan-3-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(5-chloro-8-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(5-fluoro-8-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   2-methyl-6-morpholino-1-(2-(thiazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(3-chloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(5,7-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(5-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(6,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(7,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-fluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxamide;-   2-cyclopropyl-1-(7,8-difluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   2-cyclopropyl-1-(8-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   2-ethyl-1-(8-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(3,8-dichloroquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(3,8-dichloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(3-chloro-8-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(5-chloro-8-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(6,8-difluoroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-fluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-2-cyclopropyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   2-ethyl-6-morpholino-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   2-methyl-1-(8-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   2-methyl-6-morpholino-1-(8-(trifluoromethyl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   2-methyl-6-morpholino-1-(quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-2-(2-methoxyethyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(oxazol-5-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(pyridin-2-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(thiazol-5-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(oxetan-3-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-7-fluoro-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   (S)-1-(8-chloroquinolin-4-yl)-2-methyl-6-(3-methylmorpholino)-1H-benzo[d]imidazole-4-carboxamide;-   (R)-1-(8-chloroquinolin-4-yl)-2-methyl-6-(3-methylmorpholino)-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(1H-pyrazol-5-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-2-(isothiazol-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-6-morpholino-2-(1H-pyrazol-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-5-fluoro-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   2-methyl-6-morpholino-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   tert-butyl    4-(4-(4-carbamoyl-2-methyl-6-morpholino-1H-benzo[d]imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate;-   tert-butyl    4-(4-(4-carbamoyl-2-methyl-6-morpholino-1H-benzo[d]imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate;-   1-(3-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloro-5-fluoroquinolin-4-yl)-7-fluoro-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-chloroquinolin-4-yl)-7-fluoro-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-cyano-3-methylquinolin-4-yl)-2-ethyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   1-(8-cyano-3-methylquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxamide;-   tert-butyl    4-(4-(4-carbamoyl-6-morpholino-1H-benzo[d]imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate;-   6-morpholino-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   6-morpholino-1-(2-(1-trityl-1H-pyrazol-3-yl)quinolin-4-yl)-1H-benzo[d]imidazole-4-carboxamide;-   4-(4-carbamoyl-2-ethyl-6-morpholino-1H-benzo[d]imidazol-1-yl)quinoline-3-carboxamide;-   4-(4-carbamoyl-2-methyl-6-morpholino-1H-benzo[d]imidazol-1-yl)quinoline-3-carboxamide;

Step 5:4-(1-(8-Chloroquinolin-4-yl)-2-propyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-6-yl)morpholine2,2,2-trifluoroacetate

1-(8-chloroquinolin-4-yl)-6-morpholino-2-propyl-1H-benzo[d]imidazole-4-carboxamide(60 mg, 0.13 mmol) was suspended in1,1-dimethoxy-N,N-dimethylmethanamine (2.3 mL, 17 mmol) and stirred at120° C. for 1 hour. The solution was cooled to ambient temperature andconcentrated in vacuuo. The residue was dissolved in acetic acid (1 mL)and hydrazine hydrate (8 μL, 0.17 mmol) was added. The reaction mixturewas stirred at 90° C. for 1 hour, after which the reaction was cooled toambient temperature. The resultant was purified by HPLC eluting with5-95% water/acetonitrile (0.1% v/v trifluoroacetic acid). Theappropriate fractions were pooled and lyophilized to afford4-(1-(8-chloroquinolin-4-yl)-2-propyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-6-yl)morpholine2,2,2-trifluoroacetate (Compound 1). ¹H NMR (400 MHz, DMSO-d6) δ 9.37(d, J=4.5 Hz, 1H), 8.68 (s, 1H), 8.16-8.10 (m, 2H), 7.79 (d, J=1.6 Hz,1H), 7.66-7.59 (m, 1H), 7.47 (d, J=8.8 Hz, 1H), 6.68 (d, J=2.2 Hz, 1H),3.66 (t, J=4.7 Hz, 4H), 3.09-3.02 (m, 4H), 2.88-2.80 (m, 2H), 1.62-1.45(m, 2H), 0.78 (t, J=7.4 Hz, 3H). ES/MS m/z 474.20 (M+H)⁺.

The compounds listed in the table below were prepared in a mannersimilar to that described above using appropriate intermediates andchemistry:

Compound Compound Name MS NMR 2 4-(1-(8-chloroquinolin- 502.3 1H NMR(400 MHz, DMSO-d6) δ 9.36 4-yl)-2-isobutyl-4-(5- (d, J = 4.5 Hz, 1H),8.13 (dd, J = 7.6, 1.2 methyl-4H-1,2,4- Hz, 1H), 8.10 (d, J = 4.5 Hz,1H), 7.73 triazol-3-yl)-1H- (d, J = 2.1 Hz, 1H), 7.63 (dd, J = 8.5, 7.5benzo[d]imidazol-6- Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.64yl)morpholine (d, J = 2.2 Hz, 1H), 3.65 (t, J = 4.7 Hz, 4H), 3.04 (d, J= 3.8 Hz, 4H), 2.81 (s, 1H), 2.76-2.66 (m, 1H), 2.58-2.51 (m, 3H), 2.32(s, 1H), 0.78 (d, J = 6.6 Hz, 3H), 0.73 (d, J = 6.6 Hz, 3H). 34-(1-(5,8- 490.33 1H NMR (400 MHz, DMSO-d6) δ 9.37difluoroquinolin-4-yl)- (dd, J = 4.5, 2.0 Hz, 1H), 8.17 (dd, J =4-(5-methyl-4H-1,2,4- 4.5, 1.5 Hz, 1H), 7.83 (td, J = 9.8, 3.6triazol-3-yl)-2-propyl- Hz, 1H), 7.74 (t, J = 1.8 Hz, 1H), 7.57-1H-benzo[d]imidazol- 7.48 (m, 1H), 6.81 (d, J = 2.2 Hz, 1H),6-yl)morpholine 3.67 (q, J = 3.7, 2.2 Hz, 4H), 3.10 (d, J = 5.1 Hz, 4H),2.90 (t, J = 8.1 Hz, 2H), 2.53 (d, J = 1.9 Hz, 3H), 1.57 (d, J = 8.3 Hz,2H), 0.81 (td, J = 7.3, 2.4 Hz, 3H). 4 4-(1-(8-chloroquinolin- 486.2 1HNMR (400 MHz, DMSO-d6) δ 9.36 4-yl)-2-(1- (d, J = 4.5 Hz, 1H), 8.52 (s,1H), 8.13 (d, methylcyclopropyl)-4- J = 1.4 Hz, 1H), 8.12-8.11 (m, 1H),(4H-1,2,4-triazol-3-yl)- 7.70 (d, J = 2.3 Hz, 1H), 7.62 (dd, J =1H-benzo[d]imidazol- 8.5, 7.5 Hz, 1H), 7.41 (dd, J = 8.5, 1.26-yl)morpholine Hz, 1H), 6.53 (d, J = 2.3 Hz, 1H), 3.64 (t, J = 4.8 Hz,4H), 3.06-2.98 (m, 4H), 1.39 (ddd, J = 10.2, 6.3, 4.2 Hz, 1H), 1.26 (d,J = 5.1 Hz, 1H), 1.02 (s, 3H), 0.69 (ddd, J = 8.9, 6.3, 4.1 Hz, 1H),0.55 (ddd, J = 9.0, 6.3, 4.3 Hz, 1H). 5 4-(1-(5-chloro-8- 478.22 1H NMR(400 MHz, DMSO-d6) δ 9.36 fluoroquinolin-4-yl)-2- (d, J = 4.4 Hz, 1H),8.69 (s, 1H), 8.17 (d, ethyl-4-(4H-1,2,4- J = 4.4 Hz, 1H), 7.84 (d, J =7.2 Hz, 2H), triazol-3-yl)-1H- 7.78 (d, J = 2.3 Hz, 1H), 6.79 (d, J =1.7 benzo[d]imidazol-6- Hz, 1H), 3.68 (t, J = 4.8 Hz, 4H), 3.11 (t,yl)morpholine J = 4.9 Hz, 4H), 2.87 (p, J = 7.6, 7.1 Hz, 2H), 1.18 (t, J= 7.5 Hz, 3H). 6 4-(2-(pyridin-2-yl)-1- 475.19 1H NMR (400 MHz, DMSO-d6)δ 9.14 (quinolin-4-yl)-4-(4H- (dd, J = 4.6, 2.2 Hz, 1H), 8.88 (d, J =7.9 1,2,4-triazol-3-yl)-1H- Hz, 1H), 8.31 (s, 1H), 8.20 (d, J = 8.5benzo[d]imidazol-6- Hz, 1H), 7.95-7.88 (m, 2H), 7.82-7.74 yl)morpholine(m, 3H), 7.49-7.43 (m, 1H), 7.23 (dd, J = 7.9, 4.9 Hz, 2H), 6.48 (s,1H), 3.65 (t, J = 4.8 Hz, 4H), 3.04 (q, J = 4.5 Hz, 4H). 74-(1-(7-fluoroquinolin- 458.4 1H NMR (400 MHz, DMSO-d6) δ 9.264-yl)-2-propyl-4-(4H- (dd, J = 4.7, 2.5 Hz, 1H), 8.70 (s, 1H),1,2,4-triazol-3-yl)-1H- 8.10-8.04 (m, 1H), 7.98 (dd, J = 4.7,benzo[d]imidazol-6- 2.5 Hz, 1H), 7.80 (t, J = 2.5 Hz, 1H), yl)morpholine7.68-7.55 (m, 2H), 6.62 (d, J = 2.4 Hz, 1H), 3.71-3.58 (m, 4H),3.12-2.99 (m, 4H), 2.90-2.77 (m, 2H), 1.59-1.41 (m, 2H), 0.79-0.70 (m,3H). 8 4-(1-(8-chloroquinolin- 500.3 1H NMR (400 MHz, DMSO-d6) δ 9.364-yl)-2- (d, J = 4.5 Hz, 1H), 8.16-8.11 (m, 2H), (cyclopropylmethyl)-4-7.76 (d, J = 2.2 Hz, 1H), 7.62 (dd, J = (5-methyl-4H-1,2,4- 8.5, 7.5 Hz,1H), 7.45 (d, J = 8.4 Hz, triazol-3-yl)-1H- 1H), 6.67 (d, J = 2.3 Hz,1H), 3.65 (t, J = benzo[d]imidazol-6- 4.8 Hz, 4H), 3.06 (s, 4H), 2.88(dt, J = yl)morpholine 15.2, 7.4 Hz, 2H), 2.53 (d, J = 5.9 Hz, 3H), 0.78(s, 1H), 0.27 (dd, J = 9.6, 4.3 Hz, 2H), 0.08 (ddd, J = 17.4, 8.9, 4.4Hz, 2H). 9 4-(1-(8-chloroquinolin- 502.37 1H NMR (400 MHz, DMSO-d6) δ9.35- 4-yl)-2- 9.28 (m, 1H), 8.34 (s, 1H), 8.15-8.07(tetrahydrofuran-3-yl)- (m, 1H), 8.06-7.99 (m, 1H), 7.68-7.634-(4H-1,2,4-triazol-3- (m, 1H), 7.65-7.55 (m, 1H), 7.27-7.18 yl)-1H- (m,1H), 6.63-6.56 (m, 1H), 4.22-3.98 benzo[d]imidazol-6- (m, 1H), 3.95-3.82(m, 2H), 3.70-3.56 yl)morpholine (m, 5H), 3.35-3.24 (m, 1H), 3.06-2.97(m, 4H), 2.56-2.44 (m, 0.5H), 2.39- 2.28 (m, 0.5H), 2.13-2.03 (m, 0.5H),1.85-1.75 (m, 0.5H). 10 4-(1-(8-chloroquinolin- 509.38 1H NMR (400 MHz,DMSO-d6) δ 9.29 4-yl)-2-(pyridin-3-yl)- (dd, J = 4.5, 1.7 Hz, 1H), 8.96(d, J = 1.6 4-(4H-1,2,4-triazol-3- Hz, 1H), 8.55 (dd, J = 4.9, 1.6 Hz,1H), yl)-1H- 8.36 (s, 1H), 8.08 (dd, J = 7.5, 1.2 Hz,benzo[d]imidazol-6- 1H), 8.03 (dd, J = 4.5, 1.6 Hz, 1H), 7.92yl)morpholine (dt, J = 8.1, 1.9 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.56(ddd, J = 9.2, 7.6, 1.7 Hz, 1H), 7.40-7.32 (m, 2H), 6.66 (d, J = 2.2 Hz,1H), 3.68 (t, J = 4.6 Hz, 4H), 3.14- 3.02 (m, 4H). 11 4-(1-(8-chloro-5-506.33 1H NMR (400 MHz, DMSO-d6) δ 9.44 fluoroquinolin-4-yl)-4- (t, J =4.2 Hz, 1H), 8.18 (dt, J = 8.5, 4.4 (5-methyl-4H-1,2,4- Hz, 2H), 7.75(d, J = 2.5 Hz, 1H), 7.54 triazol-3-yl)-2-propyl- (ddd, J = 12.3, 8.5,3.9 Hz, 1H), 6.85- 1H-benzo[d]imidazol- 6.80 (m, 1H), 3.67 (q, J = 4.2Hz, 4H), 6-yl)morpholine 3.14-3.06 (m, 4H), 2.91 (s, 2H), 2.55 (d, J =4.0 Hz, 3H), 1.57 (dd, J = 7.9, 3.8 Hz, 2H), 0.81 (td, J = 7.3, 3.6 Hz,3H). 12 4-(1-(8-chloroquinolin- 490.2 1H NMR (400 MHz, DMSO-d6) δ 9.33-4-yl)-2-(1- 9.27 (m, 1H), 8.43-8.30 (m, 1H), 8.13- methoxyethyl)-4-(4H-8.05 (m, 1H), 7.99-7.95 (m, 1H), 7.68- 1,2,4-triazol-3-yl)-1H- 7.63 (m,1H), 7.61-7.54 (m, 1H), 7.26- benzo[d]imidazol-6- 7.18 (m, 1H),6.61-6.48 (m, 1H), 4.67- yl)morpholine 4.35 (m, 1H), 3.70-3.61 (m, 4H),3.07- 2.96 (m, 4H), 2.95-2.78 (m, 3H), 1.57- 1.47 (m, 3H). 134-(1-(8-chloroquinolin- 500.37 1H NMR (400 MHz, DMSO-d6) δ 9.324-yl)-2-cyclobutyl-4- (d, J = 8.3 Hz, 1H), 8.12 (d, J = 4.7 Hz,(5-methyl-4H-1,2,4- 1H), 7.96 (d, J = 4.4 Hz, 1H), 7.71-7.57triazol-3-yl)-1H- (m, 2H), 7.27 (d, J = 7.6 Hz, 1H), 6.64benzo[d]imidazol-6- (s, 1H), 3.65 (s, 4H), 3.48 (s, 1H), 3.04yl)morpholine (s, 4H), 2.65 (d, J = 8.2 Hz, 2H), 2.50 (s, 3H), 2.08 (s,2H), 1.82 (s, 3H). 14 4-(1-(8-chloroquinolin- 488.2 1H NMR (400 MHz,DMSO-d6) δ 9.33 4-yl)-2-isopropyl-4-(5- (dd, J = 4.5, 1.9 Hz, 1H),8.14-8.09 (m, methyl-4H-1,2,4- 1H), 8.09-8.04 (m, 1H), 7.65-7.58 (m,triazol-3-yl)-1H- 2H), 7.27 (d, J = 8.5 Hz, 1H), 6.58 (s,benzo[d]imidazol-6- 1H), 3.65 (t, J = 4.5 Hz, 4H), 3.01 (s,yl)morpholine 4H), 2.67 (s, 1H), 2.47 (d, J = 1.8 Hz, 3H), 1.31 (dd, J =6.8, 1.8 Hz, 3H), 1.19 (dd, J = 6.9, 1.8 Hz, 3H). 154-(1-(8-chloroquinolin- 509.26 1H NMR (400 MHz, DMSO-d6) δ 9.304-yl)-2-(pyridin-4-yl)- (d, J = 4.5 Hz, 1H), 8.50 (d, J = 5.9 Hz,4-(4H-1,2,4-triazol-3- 2H), 8.19 (s, 1H), 8.08 (d, J = 7.6 Hz, yl)-1H-1H), 8.02 (d, J = 4.6 Hz, 1H), 7.77 (s, benzo[d]imidazol-6- 1H), 7.62(s, 2H), 7.59-7.52 (m, 1H), yl)morpholine 7.31 (d, J = 8.5 Hz, 1H), 6.60(s, 1H), 3.67 (t, J = 4.6 Hz, 4H), 3.13-3.01 (m, 4H). 164-(1-(8-chloroquinolin- 516.4 1H NMR (400 MHz, DMSO-d6) δ 9.294-yl)-4-(5-methyl-4H- (dd, J = 6.4, 4.5 Hz, 1H), 8.08 (ddd, J =1,2,4-triazol-3-yl)-2- 7.5, 2.6, 1.2 Hz, 1H), 7.98 (d, J = 4.5 Hz,(tetrahydrofuran-2-yl)- 1H), 7.64 (dd, J = 9.0, 2.2 Hz, 1H), 7.581H-benzo[d]imidazol- (ddd, J = 8.5, 7.4, 1.3 Hz, 1H), 7.23 (td,6-yl)morpholine J = 8.4, 7.9, 1.2 Hz, 1H), 6.52 (d, J = 2.3 Hz, 1H),5.07 (dd, J = 7.6, 5.8 Hz, 1H), 4.92 (t, J = 7.1 Hz, 1H), 3.65 (q, J =4.3 Hz, 4H), 3.59-3.29 (m, 3H), 3.02 (dd, J = 10.6, 3.9 Hz, 4H), 2.72(ddd, J = 22.0, 11.7, 5.6 Hz, 2H), 2.20-2.08 (m, 1H), 1.99-1.72 (m, 2H).17 4-(2-cyclopropyl-1- 438.26 1H NMR (400 MHz, DMSO-d6) δ 9.24(quinolin-4-yl)-4-(4H- (d, J = 4.5 Hz, 1H), 8.39 (s, 1H), 8.30-1,2,4-triazol-3-yl)-1H- 8.26 (m, 1H), 7.96-7.90 (m, 2H), 7.71-benzo[d]imidazol-6- 7.64 (m, 2H), 7.45-7.40 (m, 1H), 6.61 yl)morpholine(d, J = 2.2 Hz, 1H), 3.66 (t, J = 4.7 Hz, 4H), 3.03 (q, J = 4.0 Hz, 4H),1.63 (td, J = 8.4, 4.3 Hz, 1H), 1.39 (dt, J = 23.4, 4.8 Hz, 2H),1.00-0.81 (m, 2H). 18 4-(1-(8-chloro-6- 478.3 1H NMR (400 MHz, DMSO-d6)δ 9.34 fluoroquinolin-4-yl)-2- (d, J = 4.5 Hz, 1H), 8.30-8.24 (m, 1H),methyl-4-(5-methyl- 8.13 (d, J = 4.5 Hz, 1H), 7.82-7.78 (m,4H-1,2,4-triazol-3-yl)- 1H), 7.59 (d, J = 9.1 Hz, 1H), 6.75-6.721H-benzo[d]imidazol- (m, 1H), 3.72-3.63 (m, 4H), 3.14-3.046-yl)morpholine (m, 4H), 2.60 (s, 3H), 2.54 (dd, J = 1.5, 0.8 Hz, 3H).19 4-(2-methyl-4-(5- 426.1 1H NMR (400 MHz, DMSO-d6) δ 9.27methyl-4H-1,2,4- (d, J = 4.5 Hz, 1H), 8.31 (d, J = 8.5 Hz,triazol-3-yl)-1- 1H), 7.99 (d, J = 4.6 Hz, 1H), 7.97-7.93(quinolin-4-yl)-1H- (m, 1H), 7.81 (d, J = 2.2 Hz, 1H), 7.71-benzo[d]imidazol-6- 7.66 (m, 1H), 7.60 (d, J = 8.4 Hz, 1H),yl)morpholine 6.65-6.62 (m, 1H), 3.65 (t, J = 4.7 Hz, 4H), 3.11-2.99 (m,4H), 2.59 (s, 3H), 2.55 (s, 3H). 20 4-(2-(tert-butyl)-1-(8- 488.2 1H NMR(400 MHz, DMSO-d6) δ 9.32 chloroquinolin-4-yl)-4- (d, J = 4.5 Hz, 1H),8.40-8.34 (m, 1H), (4H-1,2,4-triazol-3-yl)- 8.11-8.06 (m, 2H), 7.62 (d,J = 2.3 Hz, 1H-benzo[d]imidazol- 1H), 7.58 (dd, J = 8.5, 7.5 Hz, 1H),7.12 6-yl)morpholine (dd, J = 8.5, 1.3 Hz, 1H), 6.33 (d, J = 2.3 Hz,1H), 3.63 (t, J = 4.8 Hz, 4H), 3.00- 2.94 (m, 4H), 1.24 (s, 9H). 214-(1-(7-fluoroquinolin- 472.3 1H NMR (400 MHz, DMSO-d6) δ 9.294-yl)-4-(5-methyl-4H- (dd, J = 4.5, 2.0 Hz, 1H), 8.09 (dt, J =1,2,4-triazol-3-yl)-2- 10.1, 2.3 Hz, 1H), 8.02 (dd, J = 4.6, 2.0propyl-1H- Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.72- benzo[d]imidazol-6-7.58 (m, 2H), 6.63 (t, J = 2.1 Hz, 1H), yl)morpholine 3.66 (q, J = 3.3,1.9 Hz, 4H), 3.14-3.03 (m, 4H), 2.96-2.84 (m, 2H), 2.55 (dt, J = 2.0,1.1 Hz, 3H), 1.50 (dd, J = 18.3, 8.3 Hz, 2H), 0.76 (td, J = 7.4, 2.2 Hz,3H). 22 4-(1-(7-fluoroquinolin- 430.34 1H NMR (400 MHz, DMSO-d6) δ 11.274-yl)-4-(5-methyl-4H- (s, 0.5H), 9.31-9.30 (m, 0.5H), 9.221,2,4-triazol-3-yl)-1H- (dd, J = 4.6, 1.6 Hz, 0.5H), 8.93 (dd, J =benzo[d]imidazol-6- 9.5, 5.5 Hz, 0.5H), 8.44 (d, J = 7.0 Hz,yl)morpholine 0.5H), 8.07 (d, J = 2.5 Hz, 0.5H), 8.04 (d, J = 2.5 Hz,0.5H), 7.95-7.92 (m, 0.5H), 7.87 (d, J = 8.7 Hz, 0.5H), 7.83 (d, J = 2.8Hz, 0.5H), 7.78 (dt, J = 7.4, 3.4 Hz, 1.5H), 7.76-7.72 (m, 1H), 7.65(td, J = 8.9, 2.5 Hz, 0.5H), 6.85 (d, J = 2.1 Hz, 0.5H), 6.46 (dd, J =7.4, 1.4 Hz, 0.5H), 3.80 (d, J = 5.0 Hz, 2H), 3.69 (t, J = 4.9 Hz, 2H),3.44 (d, J = 5.2 Hz, 2H), 3.11 (s, 2H), 2.59 (t, J = 1.0 Hz, 1.5H), 2.54(d, J = 0.7 Hz, 1.5H). 23 4-(1-(8-chloroquinolin- 523.4 1H NMR (400 MHz,DMSO-d6) δ 9.28 4-yl)-4-(5-methyl-4H- (d, J = 4.5 Hz, 1H), 8.92 (s, 1H),8.54 (d, 1,2,4-triazol-3-yl)-2- J = 4.9 Hz, 1H), 8.07 (d, J = 7.5 Hz,1H), (pyridin-3-yl)-1H- 8.02 (d, J = 4.5 Hz, 1H), 7.89 (d, J = 8.0benzo[d]imidazol-6- Hz, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.60-yl)morpholine 7.53 (m, 1H), 7.42-7.31 (m, 2H), 6.66 (s, 1H), 3.68 (s,4H), 3.08 (s, 4H), 2.50 (s, 3H). 24 4-(2-(oxetan-3-yl)-1- 454.23 1H NMR(400 MHz, DMSO-d6) δ 9.19 (quinolin-4-yl)-4-(4H- (d, J = 4.5 Hz, 1H),8.40 (s, 1H), 8.29- 1,2,4-triazol-3-yl)-1H- 8.24 (m, 1H), 7.92 (ddd, J =8.5, 6.9, 1.4 benzo[d]imidazol-6- Hz, 1H), 7.79 (d, J = 4.5 Hz, 1H),7.71 yl)morpholine (d, J = 2.2 Hz, 1H), 7.64 (ddd, J = 8.1, 6.9, 1.2 Hz,1H), 7.28-7.24 (m, 1H), 6.58 (d, J = 2.3 Hz, 1H), 5.14 (dd, J = 6.9, 5.6Hz, 1H), 5.07 (dd, J = 6.9, 5.6 Hz, 1H), 4.64 (dd, J = 8.7, 5.5 Hz, 1H),4.46 (dd, J = 8.6, 5.5 Hz, 1H), 4.25- 4.13 (m, 1H), 3.66 (t, J = 4.7 Hz,4H), 3.03 (q, J = 4.3 Hz, 4H). 25 4-(1-(8-chloroquinolin- 523.25 1H NMR(400 MHz, DMSO-d6) δ 9.32 4-yl)-4-(5-methyl-4H- (d, J = 4.5 Hz, 1H),8.64 (d, J = 6.5 Hz, 1,2,4-triazol-3-yl)-2- 2H), 8.10 (d, J = 3.4 Hz,1H), 8.04 (d, J = (pyridin-4-yl)-1H- 4.6 Hz, 1H), 7.84 (t, J = 4.9 Hz,2H), benzo[d]imidazol-6- 7.81-7.76 (m, 1H), 7.57 (s, 1H), 7.35yl)morpholine (d, J = 1.5 Hz, 1H), 6.62 (s, 1H), 3.68 (s, 4H), 3.11 (s,4H) 2.50 (s, 3H). 26 4-[3-(3,8- 508.2 1H NMR (400 MHz, DMSO-d6) δ 9.40dichloroquinolin-4-yl)- (s, 1H), 8.13 (dd, J = 7.5, 1.2 Hz, 1H),2-ethyl-7-(5-methyl- 7.70-7.57 (m, 2H), 7.29 (d, J = 8.4 Hz,4H-1,2,4-triazol-3- 1H), 6.73 (d, J = 2.2 Hz, 1H), 3.64 (t, J =yl)benzimidazol-5- 4.8 Hz, 4H), 3.03 (t, J = 4.9 Hz, 4H), yl]morpholine2.73-2.50 (m, 2H), 1.15 (t, J = 7.5 Hz, 3H). 27 4-[3-(3-chloro-8- 464.21H NMR (400 MHz, DMSO-d6) δ 9.36 fluoroquinolin-4-yl)-2- (s, 1H), 8.59(s, 1H), 7.80 (ddd, J = 10.7, methyl-7-(4H-1,2,4- 7.8, 1.2 Hz, 1H),7.77-7.60 (m, 1H), triazol-3- 7.34-7.18 (m, 1H), 6.80 (d, J = 2.2 Hz,yl)benzimidazol-5- 1H), 3.65 (dd, J = 5.8, 3.9 Hz, 4H), 3.07yl]morpholine (dd, J = 6.2, 3.7 Hz, 4H), 2.48 (s, 3H). 28 4-(1-(5,8-434.2 1H NMR (400 MHz, DMSO-d6) δ 9.29 difluoroquinolin-4-yl)- (d, J =4.5 Hz, 1H), 9.13 (s, 1H), 8.51 (s, 4-(4H-1,2,4-triazol-3- 1H), 8.06 (s,1H), 7.82 (dt, J = 9.5, 4.6 yl)-1H- Hz, 1H), 7.78 (d, J = 2.2 Hz, 1H),7.52 benzo[d]imidazol-6- (ddd, J = 12.4, 8.9, 3.9 Hz, 1H), 6.98 (d,yl)morpholine J = 2.0 Hz, 1H), 3.70 (t, J = 4.6 Hz, 4H), 3.15-3.11 (m,4H). 29 4-(1-(8-chloro-7- 450.2 1H NMR (400 MHz, DMSO-d6) δ 9.33fluoroquinolin-4-yl)-4- (dd, J = 4.6, 0.6 Hz, 1H), 9.03 (s, 1H),(4H-1,2,4-triazol-3-yl)- 8.45 (s, 1H), 8.02 (d, J = 4.6 Hz, 1H),1H-benzo[d]imidazol- 7.83-7.76 (m, 2H), 7.68 (dd, J = 9.4,6-yl)morpholine 5.7 Hz, 1H), 6.88 (d, J = 2.2 Hz, 1H), 3.69 (t, J = 4.8Hz, 4H), 3.10 (s, 4H). 30 4-(1-(8-chloroquinolin- 486.27 1H NMR (400MHz, DMSO-d6) δ 9.31 4-yl)-2-cyclobutyl-4- (d, J = 4.5 Hz, 1H), 8.47 (s,1H), 8.11 (4H-1,2,4-triazol-3-yl)- (dd, J = 7.5, 1.2 Hz, 1H), 7.96 (d, J= 4.5 1H-benzo[d]imidazol- Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.63-6-yl)morpholine 7.56 (m, 1H), 7.27 (d, J = 8.5 Hz, 1H), 6.63 (d, J = 2.3Hz, 1H), 3.69-3.58 (m, 4H), 3.53-3.36 (m, 2H), 3.08-2.96 (m, 4H),2.12-2.01 (m, 1H), 1.90-1.67 (m, 4H). 31 4-(1-(8-chloro-7- 504.2 1H NMR(400 MHz, DMSO-d6) δ 9.38 fluoroquinolin-4-yl)-2- (d, J = 4.5 Hz, 1H),8.57 (s, 1H), 8.08 (d, (cyclopropylmethyl)-4- J = 4.6 Hz, 1H), 7.79-7.71(m, 2H), (4H-1,2,4-triazol-3-yl)- 7.52 (s, 1H), 6.66 (d, 1H), 3.66 (t, J= 4.8 1H-benzo[d]imidazol- Hz, 4H), 3.09-3.02 (m, 4H), 2.91-2.746-yl)morpholine (m, 2H), 0.92-0.76 (m, 1H), 0.35-0.23 (m, 1H), 0.19-0.11(m, 1H), 0.10-0.02 (m, 1H),−0.12-−0.24 (m, 1H). 324-(1-(8-chloroquinolin- 486.2 1H NMR (400 MHz, DMSO-d6) δ 9.36 4-yl)-2-(d, J = 4.5 Hz, 1H), 8.68 (s, 1H), 8.16- (cyclopropylmethyl)-4- 8.10 (m,2H), 7.80 (d, J = 2.2 Hz, 1H), (4H-1,2,4-triazol-3-yl)- 7.67-7.58 (m,1H), 7.45 (d, J = 8.5 Hz, 1H-benzo[d]imidazol- 1H), 6.69 (d, J = 2.2 Hz,1H), 3.66 (t, J = 6-yl)morpholine 4.7 Hz, 4H), 3.10-3.04 (m, 4H), 2.96-2.78 (m, 2H), 0.87-0.74 (m, 1H), 0.34- 0.22 (m, 1H), 0.18-0.01 (m, 2H),−0.14-−0.25 (m, 1H). 33 4-(1-(8-chloro-6- 492.2 1H NMR (400 MHz,DMSO-d6) δ 9.31 fluoroquinolin-4-yl)-2- (d, J = 4.5 Hz, 1H), 8.64 (s,1H), 8.27- propyl-4-(4H-1,2,4- 8.19 (m, 1H), 8.15-8.09 (m, 1H),7.79-7.74 triazol-3-yl)-1H- (m, 1H), 7.39 (s, 1H), 6.70-6.65benzo[d]imidazol-6- (m, 1H), 3.65 (t, J = 4.8 Hz, 4H), 3.09-yl)morpholine 3.01 (m, 4H), 2.93-2.72 (m, 2H), 1.64-1.47 (m, 2H), 0.77(t, J = 7.3 Hz, 3H). 34 4-(1-(8-chloro-7- 492.2 1H NMR (400 MHz,DMSO-d6) δ 9.39 fluoroquinolin-4-yl)-2- (d, J = 4.6 Hz, 1H), 8.60 (s,1H), 8.08 (d, propyl-4-(4H-1,2,4- J = 4.5 Hz, 1H), 7.80-7.74 (m, 2H),triazol-3-yl)-1H- 7.58-7.52 (m, 1H), 6.66 (d, J = 2.3 Hz,benzo[d]imidazol-6- 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.05 (dd, J =yl)morpholine 6.4, 3.8 Hz, 4H), 2.81 (t, J = 7.7 Hz, 2H), 1.57 (dq, J =13.9, 7.0 Hz, 2H), 0.79 (t, J = 7.4 Hz, 3H). 35 4-(1-(8-chloro-6- 464.241H NMR (400 MHz, DMSO-d6) δ 9.34 fluoroquinolin-4-yl)-2- (d, J = 4.5 Hz,1H), 8.80 (s, 1H), 8.27 methyl-4-(4H-1,2,4- (ddd, J = 8.5, 2.7, 0.8 Hz,1H), 8.13 (d, J = triazol-3-yl)-1H- 4.5 Hz, 1H), 7.84 (d, J = 2.2 Hz,1H), benzo[d]imidazol-6- 7.58 (d, J = 9.1 Hz, 1H), 6.76 (d, J = 2.2yl)morpholine Hz, 1H), 3.67 (t, J = 4.8 Hz, 4H), 3.14- 3.07 (m, 4H),2.60 (s, 3H). 36 4-(1-(8-chloroquinolin- 474.2 1H NMR (400 MHz, DMSO-d6)δ 9.32 4-yl)-2-isopropyl-4- (dd, J = 4.5, 0.8 Hz, 1H), 8.33 (s, 1H),(4H-1,2,4-triazol-3-yl)- 8.11 (dd, J = 7.5, 1.1 Hz, 1H), 8.04 (d, J =1H-benzo[d]imidazol- 4.5 Hz, 1H), 7.64 (d, J = 2.7 Hz, 1H),6-yl)morpholine 7.60 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.58(s, 1H), 3.65 (t, J = 4.7 Hz, 4H), 3.01 (s, 4H), 2.85-2.78 (m, 1H), 1.33(d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H). 37 4-(1-(5-fluoro-8-472.25 1H NMR (400 MHz, DMSO-d6) δ 9.34 methylquinolin-4-yl)-2- (d, J =4.5 Hz, 1H), 8.72 (s, 1H), 8.08 (d, propyl-4-(4H-1,2,4- J = 4.5 Hz, 1H),7.84-7.77 (m, 2H), triazol-3-yl)-1H- 7.42 (dd, J = 12.5, 8.1 Hz, 1H),6.76 (d, J = benzo[d]imidazol-6- 2.3 Hz, 1H), 3.67 (t, J = 4.8 Hz, 4H),yl)morpholine 3.10 (t, J = 4.9 Hz, 4H), 2.88 (q, J = 6.8 Hz, 2H), 2.82(s, 3H), 1.55 (d, J = 8.2 Hz, 2H), 0.80 (t, J = 7.3 Hz, 3H). 384-(1-(8-chloro-7- 490.28 1H NMR (400 MHz, DMSO-d6) δ 9.36fluoroquinolin-4-yl)-2- (dd, J = 4.6, 3.3 Hz, 1H), 8.31 (s, 1H),cyclopropyl-4-(4H- 8.02 (d, J = 4.6 Hz, 1H), 7.79-7.72 (m,1,2,4-triazol-3-yl)-1H- 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.46 (dd, J =benzo[d]imidazol-6- 9.4, 5.6 Hz, 1H), 6.66 (d, J = 2.2 Hz, yl)morpholine1H), 3.69-3.64 (m, 4H), 3.03 (dd, J = 6.2, 3.6 Hz, 4H), 1.64 (tt, J =8.5, 4.8 Hz, 1H), 1.48-1.30 (m, 2H), 1.00-0.80 (m, 2H). 394-(1-(8-chloro-7- 464.2 1H NMR (400 MHz, DMSO-d6) δ 9.41fluoroquinolin-4-yl)-2- (t, J = 4.2 Hz, 1H), 8.73 (s, 1H), 8.09 (t,methyl-4-(4H-1,2,4- J = 4.2 Hz, 1H), 7.84-7.77 (m, 2H),triazol-3-yl)-1H- 7.70 (s, 1H), 6.73 (d, J = 2.4 Hz, 1H),benzo[d]imidazol-6- 3.67 (d, J = 4.6 Hz, 4H), 3.08 (s, 4H),yl)morpholine 2.58 (d, J = 3.6 Hz, 3H). 40 4-(1-(8-chloro-7- 464.2 1HNMR (400 MHz, DMSO-d6) δ 9.33 fluoroquinolin-4-yl)-4- (d, J = 4.6 Hz,1H), 9.05 (s, 1H), 8.02 (d, (5-methyl-4H-1,2,4- J = 4.6 Hz, 1H), 7.80(t, J = 9.1 Hz, 1H), triazol-3-yl)-1H- 7.74 (d, J = 2.1 Hz, 1H), 7.68(dd, J = benzo[d]imidazol-6- 9.4, 5.6 Hz, 1H), 6.86 (d, J = 2.3 Hz,yl)morpholine 1H), 3.69 (t, J = 4.8 Hz, 4H), 3.09 (s, 4H), 2.48 (s, 3H).41 4-(2-propyl-1- 440.3 1H NMR (400 MHz, DMSO-d6) δ 9.25(quinolin-4-yl)-4-(4H- (d, J = 4.5 Hz, 1H), 8.64 (s, 1H), 8.301,2,4-triazol-3-yl)-1H- (ddd, J = 8.5, 1.2, 0.6 Hz, 1H), 7.99 (d, J =benzo[d]imidazol-6- 4.5 Hz, 1H), 7.95 (ddd, J = 8.5, 6.9, yl)morpholine1.4 Hz, 1H), 7.79 (d, J = 2.2 Hz, 1H), 7.67 (ddd, J = 8.2, 6.9, 1.2 Hz,1H), 7.46 (d, J = 8.3 Hz, 1H), 6.59 (d, J = 2.3 Hz, 1H), 3.66 (t, J =4.8 Hz, 4H), 3.05 (q, J = 4.3 Hz, 4H), 2.81 (tq, J = 14.9, 7.4 Hz, 2H),1.55 (dt, J = 16.7, 7.5 Hz, 2H), 0.77 (t, J = 7.4 Hz, 3H). 424-(1-(8-fluoroquinolin- 474.2 1H NMR (400 MHz, DMSO-d6) δ 9.284-yl)-2-(2- (d, J = 4.5 Hz, 1H), 8.58 (s, 1H), 8.03 (d,methoxyethyl)-4-(4H- J = 4.5 Hz, 1H), 7.82-7.72 (m, 2H),1,2,4-triazol-3-yl)-1H- 7.64 (td, J = 8.2, 5.0 Hz, 1H), 7.20 (d, J =benzo[d]imidazol-6- 8.5 Hz, 1H), 6.64 (d, J = 2.3 Hz, 1H), yl)morpholine3.66 (t, J = 4.8 Hz, 4H), 3.57 (ddd, J = 16.0, 10.4, 6.4 Hz, 2H), 3.09(d, J = 5.3 Hz, 2H), 3.05 (q, J = 4.4 Hz, 4H), 2.98 (s, 3H). 434-(1-(5-fluoro-8- 486.31 1H NMR (400 MHz, DMSO-d6) δ 9.35methylquinolin-4-yl)-4- (dd, J = 4.4, 0.9 Hz, 1H), 8.11 (dd, J =(5-methyl-4H-1,2,4- 4.5, 0.9 Hz, 1H), 7.84-7.76 (m, 2H),triazol-3-yl)-2-propyl- 7.46-7.39 (m, 1H), 6.76 (dd, J = 2.3,1H-benzo[d]imidazol- 0.9 Hz, 1H), 3.66 (t, J = 4.8 Hz, 4H),6-yl)morpholine 3.09 (t, J = 5.0 Hz, 4H), 2.92 (q, J = 8.1 Hz, 2H),2.85-2.79 (m, 3H), 2.55 (d, J = 0.9 Hz, 3H), 1.52 (dt, J = 13.7, 6.9 Hz,2H), 0.85-0.75 (m, 3H). 44 4-(1-(5,8- 448.2 1H NMR (400 MHz, DMSO-d6) δ9.27 difluoroquinolin-4-yl)- (d, J = 4.7 Hz, 1H), 8.05 (d, J = 5.4 Hz,4-(5-methyl-4H-1,2,4- 1H), 7.85-7.77 (m, 2H), 7.71 (d, J = 2.6triazol-3-yl)-1H- Hz, 1H), 7.56-7.46 (m, 1H), 6.95 (d, J =benzo[d]imidazol-6- 2.8 Hz, 1H), 3.72-3.68 (m, 4H), 3.11 yl)morpholine(s, 4H), 2.47 (s, 3H). 45 4-(1-(5,8- 476.3 1H NMR (400 MHz, DMSO-d6) δ9.37 difluoroquinolin-4-yl)- (t, J = 4.0 Hz, 1H), 8.70 (s, 1H), 8.17 (t,2-propyl-4-(4H-1,2,4- J = 4.0 Hz, 1H), 7.88-7.77 (m, 2H),triazol-3-yl)-1H- 7.58-7.48 (m, 1H), 6.85-6.82 (m, 1H),benzo[d]imidazol-6- 3.73-3.63 (m, 4H), 3.10 (d, J = 3.9 Hz,yl)morpholine 4H), 2.90 (s, 2H), 1.64-1.52 (m, 2H), 0.82 (td, J = 7.3,3.4 Hz, 3H). 46 4-(1-(8-chloroquinolin- 488.2 1H NMR (400 MHz, DMSO-d6)δ 9.37 4-yl)-4-(5-methyl-4H- (dd, J = 4.6, 0.8 Hz, 1H), 8.16-8.11 (m,1,2,4-triazol-3-yl)-2- 2H), 7.77 (d, J = 2.4 Hz, 1H), 7.63 (ddd,propyl-1H- J = 8.3, 7.4, 0.7 Hz, 1H), 7.49 (d, J = 8.4benzo[d]imidazol-6- Hz, 1H), 6.69-6.64 (m, 1H), 3.65 (t, J =yl)morpholine 4.8 Hz, 4H), 3.05 (d, J = 3.0 Hz, 4H), 2.93-2.81 (m, 2H),2.54 (s, 3H), 1.60- 1.43 (m, 2H), 0.80-0.73 (m, 3H). 474-(1-(8-chloroquinolin- 486.2 1H NMR (400 MHz, DMSO-d6) δ 9.344-yl)-2-cyclopropyl-4- (dd, J = 7.9, 4.5 Hz, 1H), 8.13 (s, 1H),(5-methyl-4H-1,2,4- 8.04 (s, 1H), 7.69-7.57 (m, 2H), 7.37triazol-3-yl)-1H- (d, J = 9.0 Hz, 1H), 6.67 (s, 1H), 3.67 (d,benzo[d]imidazol-6- J = 7.7 Hz, 4H), 3.04 (s, 4H), 2.47 (s,yl)morpholine 3H), 1.66 (s, 1H), 1.37 (d, J = 33.2 Hz, 2H), 0.91 (d, J =42.9 Hz, 2H). 48 4-(1-(8-chloro-5- 492.2 1H NMR (400 MHz, DMSO-d6) δ9.42 fluoroquinolin-4-yl)-2- (d, J = 4.5 Hz, 1H), 8.63 (s, 1H), 8.15propyl-4-(4H-1,2,4- (td, J = 5.5, 3.8 Hz, 2H), 7.75 (s, 1H),triazol-3-yl)-1H- 7.53 (dd, J = 11.9, 8.5 Hz, 1H), 6.82 (d, J =benzo[d]imidazol-6- 2.2 Hz, 1H), 3.67 (t, J = 4.9 Hz, 4H), yl)morpholine3.09 (t, J = 4.9 Hz, 4H), 2.84 (d, J = 10.0 Hz, 2H), 1.64-1.53 (m, 2H),0.81 (t, J = 7.3 Hz, 3H). 49 4-(1-(7,8- 476.2 1H NMR (400 MHz, DMSO-d6)δ 9.33 difluoroquinolin-4-yl)- (d, J = 4.5 Hz, 1H), 8.62 (s, 1H), 8.08(d, 2-propyl-4-(4H-1,2,4- J = 4.5 Hz, 1H), 7.85-7.73 (m, 2H),triazol-3-yl)-1H- 7.44-7.36 (m, 1H), 6.65 (d, J = 2.3 Hz,benzo[d]imidazol-6- 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.10-3.02yl)morpholine (m, 4H), 2.83 (t, J = 7.7 Hz, 2H), 1.65- 1.48 (m, 2H),0.79 (t, J = 7.4 Hz, 3H). 50 4-(1-(8-chloroquinolin- 488.2 1H NMR (400MHz, DMSO-d6) δ 9.35 4-yl)-2-isobutyl-4-(4H- (d, J = 4.5 Hz, 1H), 8.55(s, 1H), 8.13 1,2,4-triazol-3-yl)-1H- (dd, J = 7.5, 1.3 Hz, 1H), 8.07(d, J = 4.5 benzo[d]imidazol-6- Hz, 1H), 7.74 (s, 1H), 7.62 (dd, J =8.5, yl)morpholine 7.5 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H),3.65 (t, J = 4.7 Hz, 4H), 3.04 (d, J = 5.7 Hz, 4H), 2.67 (s, 2H), 2.54(s, 1H), 0.79 (d, J = 6.6 Hz, 3H), 0.75 (d, J = 6.6 Hz, 3H). 514-(1-(5,8- 462.2 1H NMR (400 MHz, DMSO-d6) δ 9.38difluoroquinolin-4-yl)- (d, J = 4.5 Hz, 1H), 8.14 (d, J = 4.5 Hz,2-methyl-4-(5-methyl- 1H), 7.90-7.74 (m, 2H), 7.62-7.49 (m,4H-1,2,4-triazol-3-yl)- 1H), 6.87-6.83 (m, 1H), 3.70-3.64 (m,1H-benzo[d]imidazol- 4H), 3.11 (t, J = 4.9 Hz, 4H), 2.63 (s,6-yl)morpholine 3H), 2.55-2.53 (m, 3H). 52 4-(1-(8-chloro-7- 478.2 1HNMR (400 MHz, DMSO-d6) δ 9.40 fluoroquinolin-4-yl)-2- (d, J = 4.5 Hz,1H), 8.08 (d, J = 4.6 Hz, methyl-4-(5-methyl- 1H), 7.83-7.75 (m, 2H),7.70 (d, J = 6.7 4H-1,2,4-triazol-3-yl)- Hz, 1H), 6.70 (d, J = 2.2 Hz,1H), 3.65 1H-benzo[d]imidazol- (d, J = 4.8 Hz, 4H), 3.06 (s, 4H), 2.58(s, 6-yl)morpholine 3H), 2.53 (s, 3H). 53 4-(l-(7-fluoroquinolin- 416.321H NMR (400 MHz, DMSO-d6) δ 9.22 4-yl)-4-(4H-1,2,4- (dd, J = 4.6, 1.6Hz, 1H), 9.17 (s, 1H), triazol-3-yl)-1H- 8.53 (s, 1H), 8.05 (dd, J =10.1, 2.4 Hz, benzo[d]imidazol-6- 1H), 7.92 (dd, J = 4.6, 1.6 Hz, 1H),7.82 yl)morpholine (d, J = 2.2 Hz, 1H), 7.74 (dd, J = 9.3, 6.0 Hz, 1H),7.69-7.62 (m, 1H), 6.85 (s, 1H), 3.70 (t, J = 4.9 Hz, 4H), 3.11 (s, 4H).54 4-(1-(8-chloroquinolin- 490.2 1H NMR (400 MHz, DMSO-d6) δ 9.304-yl)-2-(1- (d, J = 4.5 Hz, 1H), 8.36 (s, 1H), 8.09fluorocyclopropyl)-4- (dd, J = 7.5, 1.2 Hz, 1H), 8.04 (d, J = 4.5(4H-1,2,4-triazol-3-yl)- Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.601H-benzo[d]imidazol- (dd, J = 8.5, 7.5 Hz, 1H), 7.32 (dd, J =6-yl)morpholine 8.5, 1.3 Hz, 1H), 6.61 (d, J = 2.3 Hz, 1H), 3.66 (t, J =4.7 Hz, 4H), 3.04 (td, J = 4.3, 2.2 Hz, 4H), 1.70 (dddd, J = 14.5, 11.2,8.5, 3.3 Hz, 2H), 1.43-1.17 (m, 2H). 55 4-[3-(2-ethyl-3- 454.2 1H NMR(400 MHz, DMSO-d6) δ 8.77 methylquinolin-4-yl)-2- (s, 1H), 8.14 (dt, J =8.2, 0.9 Hz, 1H), methyl-7-(4H-1,2,4- 7.83 (d, J = 2.2 Hz, 1H), 7.79(ddd, J = triazol-3- 8.4, 7.0, 1.4 Hz, 1H), 7.51 (ddd, J = 8.3,yl)benzimidazol-5- 6.9, 1.2 Hz, 1H), 7.25-7.18 (m, 1H), yl]morpholine6.62 (d, J = 2.2 Hz, 1H), 3.63 (t, J = 4.8 Hz, 4H), 3.17-3.00 (m, 6H),2.48 (s, 3H), 2.10 (s, 3H), 1.41 (t, J = 7.4 Hz, 3H). 564-[3-(2-cyclopropyl-3- 466.2 1H NMR (400 MHz, DMSO-d6) δ 8.81methylquinolin-4-yl)-2- (s, 1H), 8.01 (dt, J = 8.4, 0.9 Hz, 1H),methyl-7-(4H-1,2,4- 7.85 (d, J = 2.2 Hz, 1H), 7.74 (ddd, J = triazol-3-8.4, 6.9, 1.4 Hz, 1H), 7.45 (ddd, J = 8.2, yl)benzimidazol-5- 6.9, 1.2Hz, 1H), 7.22-7.15 (m, 1H), yl]morpholine 6.67 (d, J = 2.2 Hz, 1H), 3.64(t, J = 4.8 Hz, 4H), 3.09 (td, J = 4.2, 2.0 Hz, 4H), 2.55-2.49 (m, 1H),2.51 (s, 3H), 2.23 (s, 3H), 1.40-1.06 (m, 4H). 57 4-[2-methyl-7-(4H-479.2 1H NMR (400 MHz, DMSO-d6) δ 8.80 1,2,4-triazol-3-yl)-3-[2- (br s,1H), 8.65 (s, 1H), 8.57 (br s, 2H), (4H-1,2,4-triazol-3- 8.33 (dt, J =8.5, 0.9 Hz, 1H), 7.97 (ddd, yl)quinolin-4- J = 8.4, 6.8, 1.5 Hz, 1H),7.83 (d, J = 2.2 yl]benzimidazol-5- Hz, 1H), 7.67 (ddd, J = 8.2, 6.9,1.2 Hz, yl]morpholine 1H), 7.62-7.56 (m, 1H), 6.77 (d, J = 2.2 Hz, 1H),3.61 (t, J = 4.8 Hz, 4H), 3.05 (q, J = 4.5 Hz, 4H), 2.60 (s, 3H). 584-[3-[8-chloro-2- 514.1 1H NMR (400 MHz, DMSO-d6) δ 8.75(trifluoromethyl)quinolin- (br s, 1H), 8.61 (s, 1H), 8.27 (dd, J = 7.5,4-yl]-2-methyl-7- 1.2 Hz, 1H), 7.83-7.72 (m, 2H), 7.72-(4H-1,2,4-triazol-3- 7.63 (m, 1H), 6.82 (d, J = 2.2 Hz, 1H),yl)benzimidazol-5- 3.63 (t, J = 4.8 Hz, 4H), 3.04 (q, J = 4.4yl]morpholine Hz, 4H), 2.59 (s, 3H). 59 4-[2-methyl-3-(2- 488.2 1H NMR(400 MHz, DMSO-d6) δ 8.81 phenylquinolin-4-yl)-7- (br s, 1H), 8.65 (s,1H), 8.36-8.27 (m, (4H-1,2,4-triazol-3- 3H), 7.93 (ddd, J = 8.4, 6.5,1.8 Hz, 1H), yl)benzimidazol-5- 7.85 (d, J = 2.2 Hz, 1H), 7.67-7.49 (m,yl]morpholine 6H), 6.75 (d, J = 2.2 Hz, 1H), 3.62 (t, J = 4.9 Hz, 4H),3.13-2.98 (m, 4H), 2.65 (s, 3H). 60 4-[2-methyl-3-[2- 494.2 1H NMR (400MHz, DMSO-d6) δ 8.68 methyl-8- (s, 1H), 8.30-8.23 (m, 1H), 7.98 (s,(trifluoromethyl)quinolin- 1H), 7.83-7.72 (m, 2H), 7.67 (t, J = 7.94-yl]-7-(4H-1,2,4- Hz, 1H), 6.73 (d, J = 2.2 Hz, 1H), 3.63 triazol-3-(t, J = 4.8 Hz, 4H), 3.13-2.96 (m, 4H), yl)benzimidazol-5- 2.82 (s, 3H),2.54 (s, 3H). yl]morpholine 61 4-[3-(8-fluoro-2,3- 458.2 1H NMR (400MHz, DMSO-d6) δ 8.71 dimethylquinolin-4-yl)- (s, 1H), 7.85-7.77 (m, 1H),7.70-7.59 2-methyl-7-(4H-1,2,4- (m, 1H), 7.50 (td, J = 8.1, 4.9 Hz, 1H),triazol-3- 7.03 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 2.2 yl)benzimidazol-5-Hz, 1H), 3.67 (t, J = 4.8 Hz, 4H), 3.09 yl]morpholine (dt, J = 4.4, 2.5Hz, 4H), 2.84 (s, 3H), 2.49 (s, 3H), 2.13 (s, 3H). 62 4-[3-(3-ethyl-2-454.26 1H NMR (400 MHz, DMSO-d6) δ 8.74 methylquinolin-4-yl)-2- (br s,1H), 8.18-8.09 (m, 1H), 7.88- methyl-7-(4H-1,2,4- 7.75 (m, 2H), 7.53(ddd, J = 8.2, 6.9, 1.2 triazol-3- Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H),6.70 yl)benzimidazol-5- (d, J = 2.2 Hz, 1H), 3.66 (t, J = 4.8 Hz,yl]morpholine 4H), 3.09 (q, J = 4.1 Hz, 4H), 2.88 (s, 3H), 2.63-2.52 (m,2H), 2.48 (s, 3H), 1.01 (t, J = 7.5 Hz, 3H). 63 4-[3-(7-fluoro-2- 444.21H NMR (400 MHz, DMSO-d6) δ 8.75 methylquinolin-4-yl)-2- (br s, 1H),7.96 (dd, J = 10.2, 2.6 Hz, methyl-7-(4H-1,2,4- 1H), 7.88-7.79 (m, 2H),7.69-7.57 triazol-3- (m, 1H), 7.53 (td, J = 8.8, 2.6 Hz, 1H),yl)benzimidazol-5- 6.67 (d, J = 2.2 Hz, 1H), 3.67 (t, J = 4.8yl]morpholine Hz, 4H), 3.08 (q, J = 4.7 Hz, 4H), 2.80 (s, 3H), 2.58 (s,3H). 64 4-[3-(8-chloro-2- 460.2 1H NMR (400 MHz, DMSO-d6) δ 8.78methylquinolin-4-yl)-2- (s, 1H), 8.11-8.03 (m, 1H), 7.98 (s,methyl-7-(4H-1,2,4- 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.55 (dd, J =triazol-3- 8.4, 7.3 Hz, 1H), 7.52-7.44 (m, 1H), yl)benzimidazol-5- 6.74(d, J = 2.2 Hz, 1H), 3.66 (t, J = 4.8 yl]morpholine Hz, 4H), 3.16-3.00(m, 4H), 2.85 (s, 3H), 2.60 (s, 3H). 65 4-[2-methyl-3-(3- 426.2 1H NMR(400 MHz, DMSO-d6) δ 9.20 methylquinolin-4-yl)-7- (s, 1H), 8.78 (s, 1H),8.29-8.21 (m, (4H-1,2,4-triazol-3- 1H), 7.92-7.81 (m, 2H), 7.63 (ddd, J= yl)benzimidazol-5- 8.2, 6.9, 1.2 Hz, 1H), 7.43-7.35 (m, yl]morpholine1H), 6.68 (d, J = 2.2 Hz, 1H), 3.67 (t, J = 4.9 Hz, 4H), 3.17-3.05 (m,4H), 2.52 (s, 3H), 2.23 (s, 3H). 66 4-[3-(3- 452.2 1H NMR (400 MHz,DMSO-d6) δ 8.88 cyclopropylquinolin-4- (s, 1H), 8.76 (br s, 1H),8.26-8.19 (m, yl)-2-methyl-7-(4H- 1H), 7.89-7.80 (m, 2H), 7.62 (ddd, J =1,2,4-triazol-3- 8.2, 6.9, 1.2 Hz, 1H), 7.35 (d, J = 8.3 Hz,yl)benzimidazol-5- 1H), 6.70 (d, J = 2.2 Hz, 1H), 3.74- yl]morpholine3.55 (m, 4H), 3.10 (t, J = 4.8 Hz, 4H), 2.56 (s, 3H), 1.65-1.56 (m, 1H),1.11- 1.03 (m, 2H), 1.00-0.81 (m, 2H). 67 4-[2-methyl-6- 437.1 1H NMR(400 MHz, DMSO-d6) δ 8.63 morpholin-4-yl-4-(4H- (br s, 1H), 8.51 (s,1H), 8.45-8.38 (m, 1,2,4-triazol-3- 1H), 8.10 (ddd, J = 8.5, 6.9, 1.3Hz, 1H), yl)benzimidazol-1- 7.85 (ddd, J = 8.4, 6.8, 1.1 Hz, 1H), 7.77yl]quinoline-2- (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 6.76 (d, carbonitrileJ = 2.2 Hz, 1H), 3.67 (t, J = 4.9 Hz, 4H), 3.07 (q, J = 5.0 Hz, 4H),2.53 (d, J = 17.6 Hz, 3H). 68 4-[3-(8-chloro-3- 460.1 1H NMR (400 MHz,DMSO-d6) δ 9.29 methylquinolin-4-yl)-2- (s, 1H), 8.69 (br s, 1H), 8.05(dd, J = 7.5, methyl-7-(4H-1,2,4- 1.2 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H),triazol-3- 7.58 (dd, J = 8.4, 7.6 Hz, 1H), 7.32 (d, J =yl)benzimidazol-5- 8.2 Hz, 1H), 6.70 (d, J = 2.2 Hz, 1H), yl]morpholine3.71-3.61 (m, 4H), 3.13-3.06 (m, 4H), 2.49 (s, 3H), 2.23 (s, 3H). 694-[2-methyl-3-(2- 426.2 1H NMR (400 MHz, DMSO-d6) δ 13.94methylquinolin-4-yl)-7- (s, 1H), 11.95 (s, 1H), 8.18-8.09 (m,(4H-1,2,4-triazol-3- 2H), 7.84 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H),yl)benzimidazol-5- 7.78-7.73 (m, 1H), 7.62-7.51 (m, yl]morpholine 2H),7.19 (dd, J = 8.2, 1.3 Hz, 1H), 6.54 (s, 1H), 3.66 (t, J = 4.8 Hz, 4H),3.07- 2.94 (m, 4H), 2.80 (s, 3H), 2.37 (s, 3H), 1.91 (s, 3H). 704-[3-(8-chloro-2,3- 474.16 1H NMR (400 MHz, DMSO-d6) δ 8.75dimethylquinolin-4-yl)- (s, 1H), 7.99 (dd, J = 7.6, 1.2 Hz, 1H),2-methyl-7-(4H-1,2,4- 7.84 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = triazol-3-8.3, 7.6 Hz, 1H), 7.21 (dd, J = 8.4, 1.2 yl)benzimidazol-5- Hz, 1H),6.70 (d, J = 2.2 Hz, 1H), 3.67 yl]morpholine (t, J = 4.8 Hz, 4H),3.16-3.04 (m, 4H), 2.86 (s, 3H), 2.51 (s, 3H), 2.13 (s, 3H). 714-[3-(3-ethyl-2- 440.2 1H NMR (400 MHz, DMSO-d6) δ 9.10methylquinolin-4-yl)-7- (s, 1H), 8.51 (s, 1H), 8.16-8.09 (m,(4H-1,2,4-triazol-3- 1H), 7.85-7.76 (m, 2H), 7.52 (ddd, J =yl)benzimidazol-5- 8.2, 6.7, 1.2 Hz, 1H), 7.02 (dd, J = 8.3,yl]morpholine 0.9 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H), 3.67 (dd, J = 6.0,3.6 Hz, 4H), 3.08 (t, J = 4.8 Hz, 4H), 2.87 (s, 3H), 2.67-2.55 (m, 1H),2.48-2.34 (m, 1H), 1.04 (t, J = 7.5 Hz, 3H). 72 4-[3-(2-ethyl-3- 440.21H NMR (400 MHz, DMSO-d6) δ 9.36 methylquinolin-4-yl)-7- (s, 1H), 8.67(s, 1H), 8.20-8.13 (m, (4H-1,2,4-triazol-3- 1H), 7.88 (d, J = 2.3 Hz,1H), 7.81 (ddd, yl)benzimidazol-5- J = 8.4, 6.9, 1.4 Hz, 1H), 7.54 (ddd,J = yl]morpholine 8.2, 6.9, 1.2 Hz, 1H), 7.22-7.15 (m, 1H), 6.72 (d, J =2.2 Hz, 1H), 3.68 (t, J = 4.8 Hz, 4H), 3.22-3.06 (m, 6H), 2.16 (s, 3H),1.43 (t, J = 7.4 Hz, 3H). 73 4-[2-methyl-3-(2- 440.2 1H NMR (400 MHz,DMSO-d6) δ 8.20 methylquinolin-4-yl)-7- (d, J = 8.5 Hz, 1H), 7.95-7.86(m, 2H), (3-methyl-1H-1,2,4- 7.82 (d, J = 2.0 Hz, 1H), 7.65-7.57 (m,triazol-5- 1H), 7.56-7.50 (m, 1H), 6.69-6.63 yl)benzimidazol-5- (m, 1H),3.66 (t, J = 4.8 Hz, 4H), 3.15- yl]morpholine 3.00 (m, 4H), 2.81 (s,3H), 2.62 (s, 3H), 2.56 (s, 3H). 74 4-[2-methyl-3-(3- 440.2 1H NMR (400MHz, DMSO-d6) δ 9.20 methylquinolin-4-yl)-7- (s, 1H), 8.26 (d, J = 8.7Hz, 1H), 7.92- (3-methyl-1H-1,2,4- 7.84 (m, 1H), 7.84-7.79 (m, 1H),7.70- triazol-5- 7.58 (m, 1H), 7.44-7.36 (m, 1H), yl)benzimidazol-5-6.67 (d, J = 2.4 Hz, 1H), 3.66 (t, J = 4.7 yl]morpholine Hz, 4H), 3.10(dd, J = 6.3, 3.7 Hz, 4H), 2.56 (s, 3H), 2.54 (s, 3H), 2.23 (s, 3H). 754-[3-(3-ethyl-2- 454.29 1H NMR (400 MHz, DMSO-d6) δ 9.15methylquinolin-4-yl)-7- (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.80 (t,(3-methyl-1H-1,2,4- J = 7.8 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H),triazol-5- 7.56-7.47 (m, 1H), 7.02 (d, J = 8.4 Hz, yl)benzimidazol-5-1H), 6.68 (d, J = 2.2 Hz, 1H), 3.70- yl]morpholine 3.63 (m, 4H),3.09-3.03 (m, 4H), 2.87 (s, 3H), 2.65-2.57 (m, 1H), 2.45-2.35 (m, 1H),1.04 (t, J = 7.5 Hz, 3H). 76 4-[3-(2-ethyl-3- 468.3 1H NMR (400 MHz,DMSO-d6) δ 8.17 methylquinolin-4-yl)-2- (d, J = 8.4 Hz, 1H), 7.86-7.76(m, 2H), methyl-7-(3-methyl- 7.58-7.49 (m, 1H), 7.21 (d, J = 8.3 Hz,1H-1,2,4-triazol-5- 1H), 6.61 (s, 1H), 3.66 (t, J = 4.8 Hz,yl)benzimidazol-5- 4H), 3.18-3.10 (m, 2H), 3.10-3.03 yl]morpholine (m,4H), 2.54 (s, 3H), 2.13 (s, 3H), 1.45 (t, J = 7.4 Hz, 3H). 774-[2-methyl-7-(3- 508.33 1H NMR (400 MHz, DMSO-d6) δ 8.31methyl-1H-1,2,4- (d, J = 7.3 Hz, 1H), 8.02 (s, 1H), 7.82 (d,triazol-5-yl)-3-[2- J = 8.5 Hz, 1H), 7.78 (d, J = 2.2 Hz, 1H), methyl-8-7.70 (t, J = 7.9 Hz, 1H), 6.75 (d, J = 2.2 (trifluoromethyl)quinolin-Hz, 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.15- 4-yl]benzimidazol- 3.00 (m,4H), 2.85 (s, 3H), 2.59 (s, 3H), 5-yl]morpholine 2.54 (s, 3H). 784-[3-(8-chloro-3- 474.25 1H NMR (400 MHz, DMSO-d6) δ 9.29methylquinolin-4-yl)-2- (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.76 (s,methyl-7-(3-methyl- 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.32 (d, J =1H-1,2,4-triazol-5- 8.4 Hz, 1H), 6.69 (d, J = 2.2 Hz, 1H),yl)benzimidazol-5- 3.66 (t, J = 4.9 Hz, 4H), 3.08 (t, J = 4.9yl]morpholine Hz, 4H), 2.53 (s, 3H), 2.23 (s, 3H). 79 4-[3-(7-fluoro-2-458.29 1H NMR (400 MHz, DMSO-d6) δ 7.97 methylquinolin-4-yl)-2- (dd, J =10.2, 2.5 Hz, 1H), 7.86 (s, 1H), methyl-7-(3-methyl- 7.80 (d, J = 2.3Hz, 1H), 7.69-7.61 (m, 1H-1,2,4-triazol-5- 1H), 7.53 (td, J = 8.8, 2.6Hz, 1H), 6.66 yl)benzimidazol-5- (d, J = 2.3 Hz, 1H), 3.66 (t, J = 4.8Hz, yl]morpholine 4H), 3.15-2.98 (m, 4H), 2.80 (s, 3H), 2.61 (s, 3H),2.54 (s, 3H). 80 4-[3-(2-ethyl-8-fluoro- 486.3 1H NMR (400 MHz, DMSO-d6)δ 7.75 3-methylquinolin-4-yl)- (s, 1H), 7.69-7.60 (m, 1H), 7.50 (td, J =2-methyl-7-(3-methyl- 8.0, 4.8 Hz, 1H), 7.00 (d, J = 8.5 Hz,1H-1,2,4-triazol-5- 1H), 6.65 (s, 1H), 3.66 (t, J = 4.8 Hz,yl)benzimidazol-5- 4H), 3.15 (q, J = 15.0, 7.8 Hz, 2H), 3.10-yl]morpholine 3.04 (m, 4H), 2.52 (s, 3H), 2.47 (s, 3H), 2.13 (s, 3H),1.45 (t, J = 7.3 Hz, 3H). 81 4-[3-(5-fluoroquinolin- 430.2 1H NMR (400MHz, DMSO-d6) δ 9.31 4-yl)-2-methyl-7-(4H- (d, J = 4.5 Hz, 1H),8.20-8.16 (m, 1H), 1,2,4-triazol-3- 8.00 (d, J = 4.5 Hz, 1H), 7.94 (td,J = yl)benzimidazol-5- 8.3, 5.8 Hz, 1H), 7.78 (s, 1H), 7.52 (dd, J =yl]morpholine 12.4, 7.9 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H), 3.67 (t, J =4.8 Hz, 4H), 3.10 (t, J = 5.0 Hz, 4H), 2.57 (s, 3H). 82 4-[3-[8- 462.11H NMR (400 MHz, DMSO-d6) δ 9.34 (difluoromethyl)quinolin- (d, J = 4.5Hz, 1H), 8.20 (d, J = 7.0 Hz, 4-yl]-2-methyl-7- 1H), 8.14-7.82 (m, 2H),7.82-7.71 (4H-1,2,4-triazol-3- (m, 3H), 6.68 (d, J = 2.2 Hz, 1H), 3.64yl)benzimidazol-5- (t, J = 4.7 Hz, 4H), 3.05 (q, J = 4.2 Hz,yl]morpholine 4H), 2.53 (d, J = 6.2 Hz, 3H). 83 4-[2-methyl-3-(5- 426.21H NMR (400 MHz, DMSO-d6) δ 9.21 methylquinolin-4-yl)-7- (d, J = 4.4 Hz,1H), 8.73 (s, 1H), 8.21- (4H-1,2,4-triazol-3- 8.15 (m, 1H), 7.90-7.80(m, 3H), 7.57- yl)benzimidazol-5- 7.50 (m, 1H), 6.69 (d, J = 2.2 Hz,1H), yl]morpholine 3.67 (t, J = 4.8 Hz, 4H), 3.15-3.07 (m, 4H), 2.55 (s,3H), 1.82 (s, 3H). 84 4-[3-(5-chloroquinolin- 446.1 1H NMR (400 MHz,DMSO-d6) δ 9.32 4-yl)-2-methyl-7-(4H- (d, J = 4.5 Hz, 1H), 8.83-8.53 (m,1H), 1,2,4-triazol-3- 8.33 (dd, J = 8.5, 1.2 Hz, 1H), 8.01 (d, J =yl)benzimidazol-5- 4.5 Hz, 1H), 7.96-7.90 (m, 1H), 7.84 yl]morpholine(dd, J = 7.7, 1.2 Hz, 1H), 7.81-7.77 (m, 1H), 6.77-6.75 (m, 1H), 3.67(t, J = 4.9 Hz, 4H), 3.11 (t, J = 4.9 Hz, 4H), 2.54 (s, 3H). 85 4-[3-[5-462.1 1H NMR (400 MHz, DMSO-d6) δ 9.29 (difluoromethyl)quinolin- (d, J =4.5 Hz, 1H), 8.64 (s, 1H), 8.54- 4-yl]-2-methyl-7- 8.48 (m, 1H),8.13-8.02 (m, 2H), 7.96 (4H-1,2,4-triazol-3- (d, J = 4.5 Hz, 1H), 7.77(d, J = 2.2 Hz, yl)benzimidazol-5- 1H), 6.71 (d, J = 2.2 Hz, 1H), 6.30(t, J = yl]morpholine 54.8 Hz, 1H), 3.65 (t, J = 4.7 Hz, 4H), 3.07 (q, J= 4.0 Hz, 4H), 2.45 (s, 3H). 86 4-[3-(8-chloroquinolin- 464.1 1H NMR(400 MHz, DMSO-d6) δ 9.33 4-yl)-6-fluoro-2- (d, J = 4.5 Hz, 1H), 8.63(s, 1H), 8.11 methyl-7-(4H-1,2,4- (dd, J = 7.5, 1.2 Hz, 1H), 8.01 (d, J= 4.5 triazol-3- Hz, 1H), 7.61 (dd, J = 8.5, 7.5 Hz, 1H),yl)benzimidazol-5- 7.40 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 6.9yl]morpholine Hz, 1H), 3.65 (t, J = 4.6 Hz, 4H), 2.93- 2.76 (m, 4H),2.42 (s, 3H). 87 4-[3-(8-chloro-5- 464.1 1H NMR (400 MHz, DMSO-d6) δ9.42 fluoroquinolin-4-yl)-2- (d, J = 4.5 Hz, 1H), 8.74 (s, 1H), 8.18-methyl-7-(4H-1,2,4- 8.10 (m, 2H), 7.80 (d, J = 2.2 Hz, 1H), triazol-3-7.52 (dd, J = 11.9, 8.6 Hz, 1H), 6.87 (d, J = yl)benzimidazol-5- 2.2 Hz,1H), 3.65 (dd, J = 5.9, 3.7 Hz, yl]morpholine 5H), 3.10 (dd, J = 6.1,3.7 Hz, 4H), 2.61 (s, 3H). 88 4-[3-[8-chloro-2- 482.1 1H NMR (400 MHz,DMSO-d6) δ 8.94 (difluoromethyl)quinolin- (s, 1H), 8.39 (s, 1H), 8.29(s, 1H), 8.21 4-yl]-7-(4H-1,2,4- (dt, J = 7.5, 1.0 Hz, 1H), 7.75 (s,1H), triazol-3- 7.72 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 8.5yl)benzimidazol-5- Hz, 1H), 7.31 (t, J = 54.0 Hz, 1H), 6.86yl]morpholine (d, J = 2.3 Hz, 1H), 3.70-3.64 (m, 4H), 3.10-3.02 (m, 4H).89 4-[2-methyl-6- 437.2 1H NMR (400 MHz, DMSO-d6) δ 9.42morpholin-4-yl-4-(4H- (d, J = 4.6 Hz, 1H), 8.56-8.51 (m, 1H),1,2,4-triazol-3- 8.12 (d, J = 4.5 Hz, 1H), 7.86 (s, 1H),yl)benzimidazol-1- 7.82-7.73 (m, 2H), 6.69 (s, 1H), 3.70-yl]quinoline-8- 3.60 (m, 4H), 3.08-3.00 (m, 4H), 2.48 carbonitrile (s,3H). 90 4-[3-(7-fluoroquinolin- 430.2 1H NMR (400 MHz, DMSO-d6) δ 9.274-yl)-2-methyl-7-(4H- (d, J = 4.5 Hz, 1H), 8.77 (s, 1H), 8.071,2,4-triazol-3- (dd, J = 10.0, 2.5 Hz, 1H), 7.95 (d, J =yl)benzimidazol-5- 4.6 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), yl]morpholine7.76-7.69 (m, 1H), 7.61 (td, J = 8.7, 2.5 Hz, 1H), 6.66 (d, J = 2.2 Hz,1H), 3.65 (t, J = 4.7 Hz, 4H), 3.07 (d, J = 3.5 Hz, 4H), 2.58 (s, 3H).91 4-[3-(8-chloroquinolin- 464.2 1H NMR (400 MHz, DMSO-d6) δ 9.294-yl)-4-fluoro-2- (dd, J = 4.5, 1.6 Hz, 1H), 8.38 (s, 1H),methyl-7-(4H-1,2,4- 8.14-8.07 (m, 2H), 7.70-7.59 (m, triazol-3- 3H),7.41 (dd, J = 8.4, 1.6 Hz, 1H), 3.63 yl)benzimidazol-5- (t, J = 4.3 Hz,4H), 3.02-2.84 (m, 4H), yl]morpholine 2.45 (s, 3H). 92 4-[3-[8- 476.3 1HNMR (400 MHz, DMSO-d6) δ 9.35 (difluoromethyl)quinolin- (dd, J = 4.5,1.3 Hz, 1H), 8.22-8.18 (d, 4-yl]-2-methyl-7-(5- J = 4.7 Hz, 1H),8.14-7.83 (m, 2H), methyl-4H-1,2,4- 7.83-7.75 (m, 4H), 6.68 (d, J = 2.1Hz, triazol-3- 1H), 3.64 (t, J = 4.7 Hz, 4H), 3.09-3.00yl)benzimidazol-5- (m, 4H), 2.57 (d, J = 1.3 Hz, 3H), 2.52 yl]morpholine(d, J = 1.4 Hz, 3H). 93 4-[2-methyl-3-(5- 440.5 1H NMR (400 MHz,DMSO-d6) δ 9.19 methylquinolin-4-yl)-7- (d, J = 4.4 Hz, 1H), 8.16 (d, J= 8.4 Hz, (5-methyl-4H-1,2,4- 1H), 7.84 (d, J = 4.4 Hz, 1H), 7.81 (dd, J= triazol-3- 8.5, 7.1 Hz, 1H), 7.75 (s, 1H), 7.51 (d, yl)benzimidazol-5-J = 7.2 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), yl]morpholine 3.64 (t, J =4.8 Hz, 5H), 3.13-3.02 (m, 4H), 2.52 (s, 3H), 2.51 (s, 2H), 1.79 (s,3H). 94 4-[3-(8-chloro-5- 478.4 1H NMR (400 MHz, DMSO-d6) δ 9.40fluoroquinolin-4-yl)-2- (d, J = 4.5 Hz, 1H), 8.17-8.07 (m, 2H),methyl-7-(5-methyl- 7.71 (s, 1H), 7.51 (dd, J = 11.9, 8.5 Hz,4H-1,2,4-triazol-3- 1H), 6.81 (s, 1H), 3.70-3.60 (m, 4H),yl)benzimidazol-5- 3.11-3.01 (m, 4H), 2.57 (s, 3H). yl]morpholine 954-[3-(8-fluoroquinolin- 416.2 1H NMR (400 MHz, DMSO-d6) δ 9.214-yl)-7-(4H-1,2,4- (d, J = 4.5 Hz, 1H), 9.06 (s, 1H), 8.46 (s,triazol-3- 1H), 8.00 (d, J = 4.6 Hz, 1H), 7.81- yl)benzimidazol-5- 7.70(m, 2H), 7.66 (td, J = 8.1, 5.1 Hz, yl]morpholine 1H), 7.42 (dt, J =8.4, 1.0 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 3.68 (t, J = 4.8 Hz, 4H),3.09 (d, J = 5.2 Hz, 4H). 96 4-[3-(5-chloro-8- 450.1 1H NMR (400 MHz,DMSO-d6) δ 9.29 fluoroquinolin-4-yl)-7- (d, J = 4.5 Hz, 1H), 9.19 (s,1H), 8.54 (d, (4H-1,2,4-triazol-3- J = 6.7 Hz, 1H), 8.10-8.00 (m, 1H),yl)benzimidazol-5- 7.85-7.76 (m, 3H), 6.89 (d, J = 2.3 Hz, yl]morpholine1H), 3.67 (t, J = 4.8 Hz, 4H), 3.11 (t, J = 5.0 Hz, 4H). 97 4-[3-(3,8-480.1 1H NMR (400 MHz, DMSO-d6) δ 9.42 dichloroquinolin-4-yl)- (s, 1H),8.51 (s, 1H), 8.14 (dd, J = 7.6, 2-methyl-7-(4H-1,2,4- 1.2 Hz, 1H), 7.66(dd, J = 8.5, 7.6 Hz, triazol-3- 2H), 7.38 (d, J = 8.4 Hz, 1H), 6.78 (d,J = yl)benzimidazol-5- 2.2 Hz, 1H), 3.72-3.51 (m, 4H), 3.05yl]morpholine (t, J = 5.0 Hz, 4H), 2.43 (s, 3H). 98 4-[3-(3,8- 494.1 1HNMR (400 MHz, DMSO-d6) δ 9.40 dichloroquinolin-4-yl)- (s, 1H), 8.45 (s,1H), 8.13 (dd, J = 7.6, 2-ethyl-7-(4H-1,2,4- 1.2 Hz, 1H), 7.70-7.61 (m,2H), 7.30 triazol-3- (d, J = 8.5 Hz, 1H), 6.75 (d, J = 2.3 Hz,yl)benzimidazol-5- 1H), 3.64 (t, J = 4.9 Hz, 4H), 3.17-2.92yl]morpholine (m, 4H), 2.64 (q, J = 7.5 Hz, 2H), 1.17 (t, J = 7.5 Hz,3H). 99 (3S)-4-[3-(8- 460.3 1H NMR (400 MHz, DMSO-d6) δ 9.35chloroquinolin-4-yl)-2- (dd, J = 4.5, 1.9 Hz, 0.5H), 8.71 (s,methyl-7-(4H-1,2,4- 0.5H), 8.16-8.03 (m, 1H), 7.80-7.70 triazol-3- (m,1H), 7.67-7.49 (m, 1H), 6.70- yl)benzimidazol-5-yl]- 6.55 (m, 1H),3.89-3.75 (m, 2H), 3.62- 3-methylmorpholine 3.40 (m, 3H), 3.15-2.84 (m,2H), 2.60- 2.51 (mz, 3H), 0.96-0.82 (m, 3H). 100 (3R)-4-[3-(8- 460.3 1HNMR (400 MHz, DMSO-d6) δ 9.35 chloroquinolin-4-yl)-2- (dd, J = 4.5, 1.9Hz, 0.5H), 8.71 (s, methyl-7-(4H-1,2,4- 0.5H), 8.16-8.03 (m, 1H),7.80-7.70 triazol-3- (m, 1H), 7.67-7.49 (m, 1H), 6.70-yl)benzimidazol-5-yl]- 6.55 (m, 1H), 3.89-3.75 (m, 2H), 3.62-3-methylmorpholine 3.40 (m, 3H), 3.15-2.84 (m, 2H), 2.60- 2.51 (mz, 3H),0.96-0.82 (m, 3H). 101 4-[3-(8-chloroquinolin- 446.1 1H NMR (400 MHz,DMSO-d6) δ 9.37 4-yl)-2-methyl-7-(4H- (dd, J = 4.5, 0.6 Hz, 1H), 8.77(s, 1H), 1,2,4-triazol-3- 8.15 (dd, J = 7.4, 1.3 Hz, 1H), 8.09 (d, J =yl)benzimidazol-5- 4.5 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), yl]morpholine7.64 (dd, J = 8.4, 7.5 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 6.73 (d, J =2.3 Hz, 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.08 (q, J = 3.9 Hz, 4H), 2.59(s, 3H). 102 4-[3-(8-chloroquinolin- 502.2 1H NMR (400 MHz, DMSO-d6) δ9.30 4-yl)-2-(oxolan-2-yl)- (d, J = 4.5 Hz, 0.5H), 9.28 (d, J = 4.5 Hz,7-(4H-1,2,4-triazol-3- 0.5H), 8.46 (s, 0.5H), 8.41 (s, 0.5H),yl)benzimidazol-5- 8.09 (dd, J = 3.7, 1.2 Hz, 0.5H), 8.08- yl]morpholine8.06 (m, 0.5H), 8.00-7.96 (m, 1H), 7.71-7.67 (m, 1H), 7.60-7.54 (m, 1H),7.27-7.21 (m, 1H), 6.61 (d, J = 2.3 Hz, 0.5H), 6.52 (d, J = 2.3 Hz, 1H),5.07 (dd, J = 7.6, 5.7 Hz, 0.5H), 4.90 (t, J = 7.0 Hz, 0.5H), 3.65 (q, J= 4.5 Hz, 4H), 3.55 (td, J = 7.7, 5.2 Hz, 0.5H), 3.52-3.32 (m, 1.5H),3.03 (dq, J = 12.1, 4.2 Hz, 4H), 2.89-2.68 (m, 1H), 2.20- 2.06 (m, 1H),2.04-1.85 (m, 1H), 1.85- 1.70 (m, 1H). 103 4-(2-methyl-1-(2- 495.20 1HNMR (400 MHz, DMSO-d6) δ 9.34- (thiazol-4-yl)quinolin- 9.32 (m, 1H),8.74-8.73 (m, 1H), 4-yl)-4-(4H-1,2,4- 8.71 (s, 1H), 8.33-8.28 (m, 1H),7.99- triazol-3-yl)-1H- 7.92 (m, 1H), 7.86-7.84 (m, 1H), 7.69-benzo[d]imidazol-6- 7.62 (m, 1H), 7.60-7.53 (m, 1H), yl)morpholine6.79-6.76 (m, 1H), 3.67-3.61 (m, 4H), 3.11-3.04 (m, 4H), 2.62 (s, 3H).104 4-(2-methyl-4-(5- 509.2 1H NMR (400 MHz, DMSO-d6) δ 9.33methyl-4H-1,2,4- (d, J = 2.0 Hz, 1H), 8.73 (d, J = 2.0 Hz,triazol-3-yl)-1-(2- 1H), 8.69 (s, 1H), 8.33-8.29 (m, 1H),(thiazol-4-yl)quinolin- 7.98-7.93 (m, 1H), 7.78 (s, 1H), 7.68- 4-yl)-1H-7.62 (m, 1H), 7.53 (s, 1H), 6.74 (s, 1H), benzo[d]imidazol-6- 3.64 (t, J= 4.8 Hz, 4H), 3.09-3.03 (m, yl)morpholine 4H), 2.60 (s, 3H), 2.53 (s,3H). 105 4-[3-(8-chloroquinolin- 460.2 1H NMR (400 MHz, DMSO-d6) δ 9.364-yl)-2-ethyl-7-(4H- (d, J = 4.5 Hz, 1H), 8.70-8.60 (m, 1H),1,2,4-triazol-3- 8.17-8.07 (m, 2H), 7.78 (d, J = 2.2 Hz,yl)benzimidazol-5- 1H), 7.67-7.59 (m, 1H), 7.51-7.41 yl]morpholine (m,1H), 6.68 (d, J = 2.3 Hz, 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.11-3.00 (m,4H), 2.90-2.80 (m, 2H), 1.11 (t, J = 7.5 Hz, 3H). 106 4-[2-methyl-3-412.2 1H NMR (400 MHz, DMSO-d6) δ 9.29- quinolin-4-yl-7-(4H- 9.24 (m,1H), 8.79 (s, 1H), 8.34-8.27 1,2,4-triazol-3- (m, 1H), 8.00-7.93 (m,2H), 7.87- yl)benzimidazol-5- 7.84 (m, 1H), 7.71-7.66 (m, 1H), 7.62-yl]morpholine 7.58 (m, 1H), 6.66 (d, J = 2.2 Hz, 1H), 3.66 (t, J = 4.8Hz, 4H), 3.12-3.05 (m, 4H), 2.59 (s, 3H). 107 4-[2-ethyl-3-quinolin-426.2 1H NMR (400 MHz, DMSO-d6) δ 9.26 4-yl-7-(4H-1,2,4- (d, J = 4.5 Hz,1H), 8.68 (s, 1H), 8.30 triazol-3- (dd, J = 8.4, 1.0 Hz, 1H), 8.01 (d, J= 4.5 yl)benzimidazol-5- Hz, 1H), 7.98-7.91 (m, 1H), 7.80 (d, J =yl]morpholine 2.2 Hz, 1H), 7.71-7.64 (m, 1H), 7.50 (d, J = 8.4 Hz, 1H),6.62 (d, J = 2.2 Hz, 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.12-3.00 (m, 4H),2.86 (q, J = 7.4 Hz, 2H), 1.10 (t, J = 7.5 Hz, 3H). 1084-[2-methyl-7-(4H- 480.2 1H NMR (400 MHz, DMSO-d6) δ 9.421,2,4-triazol-3-yl)-3-[8- (d, J = 4.6 Hz, 1H), 8.82-8.69 (m, 1H),(trifluoromethyl)quinolin- 8.38 (d, J = 7.3 Hz, 1H), 8.14 (d, J = 4.54-yl]benzimidazol- Hz, 1H), 7.97-7.87 (m, 1H), 7.87- 5-yl]morpholine7.76 (m, 2H), 6.81-6.74 (m, 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.14-3.04 (m,4H), 2.58 (s, 3H). 109 4-[2-methyl-3-(8- 426.2 1H NMR (400 MHz, DMSO-d6)δ 9.30- methylquinolin-4-yl)-7- 9.26 (m, 1H), 8.86-8.75 (m, 1H),(4H-1,2,4-triazol-3- 7.99 (d, J = 4.5 Hz, 1H), 7.86 (d, J = 2.2yl)benzimidazol-5- Hz, 1H), 7.82 (d, J = 7.1 Hz, 1H), 7.61-yl]morpholine 7.52 (m, 1H), 7.44-7.38 (m, 1H), 6.65 (d, J = 2.2 Hz, 1H),3.66 (t, J = 4.8 Hz, 4H), 3.12-3.04 (m, 4H), 2.86 (s, 3H), 2.58 (s, 3H).110 4-[3-(8-chloroquinolin- 472.1 1H NMR (400 MHz, DMSO-d6) δ 9.344-yl)-2-cyclopropyl-7- (d, J = 4.5 Hz, 1H), 8.40 (s, 1H), 8.15-(4H-1,2,4-triazol-3- 8.10 (m, 1H), 8.05 (d, J = 4.5 Hz, 1H),yl)benzimidazol-5- 7.67-7.60 (m, 2H), 7.39 (dd, J = 8.4, yl]morpholine1.2 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H), 3.66 (t, J = 4.8 Hz, 4H),3.09-2.98 (m, 4H), 1.70-1.61 (m, 1H), 1.49-1.30 (m, 2H), 1.02-0.80 (m,2H). 111 4-[3-(8-chloroquinolin- 432.1 1H NMR (400 MHz, DMSO-d6) δ 9.304-yl)-7-(4H-1,2,4- (d, J = 4.6 Hz, 1H), 9.12 (s, 1H), 8.50 (s,triazol-3- 1H), 8.14 (dd, J = 7.4, 1.3 Hz, 1H), 8.04 yl)benzimidazol-5-(d, J = 4.6 Hz, 1H), 7.81 (d, J = 2.3 Hz, yl]morpholine 1H), 7.69-7.62(m, 1H), 7.61-7.56 (m, 1H), 6.87 (d, J = 2.3 Hz, 1H), 3.69 (t, J = 4.8Hz, 4H), 3.13-3.07 (m, 4H). 112 4-[3-(8-chloroquinolin- 499.1 1H NMR(400 MHz, DMSO-d6) δ 9.26 4-yl)-2-(1,3-oxazol-5- (d, J = 4.5 Hz, 1H),9.07 (s, 1H), 8.30 (s, yl)-7-(4H-1,2,4-triazol- 1H), 8.20-8.16 (m, 1H),8.04 (dd, J = 3-yl)benzimidazol-5- 7.5, 1.2 Hz, 1H), 7.93 (d, J = 4.5Hz, yl]morpholine 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.54- 7.48 (m, 1H),7.24 (dd, J = 8.5, 1.2 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 3.67 (t, J =4.7 Hz, 4H), 3.09-3.02 (m, 4H). 113 4-[3-(8-chloroquinolin- 488.1 1H NMR(400 MHz, DMSO-d6) δ 9.28 4-yl)-2-(oxetan-3-yl)-7- (d, J = 4.4 Hz, 1H),8.33 (s, 1H), 8.10 (4H-1,2,4-triazol-3- (dd, J = 7.5, 1.2 Hz, 1H), 7.88(d, J = 4.5 yl)benzimidazol-5- Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.63-yl]morpholine 7.55 (m, 1H), 7.20 (dd, J = 8.5, 1.2 Hz, 1H), 6.61 (d, J =2.3 Hz, 1H), 5.19- 5.12 (m, 1H), 5.10-5.03 (m, 1H), 4.66 (dd, J = 8.6,5.5 Hz, 1H), 4.47 (dd, J = 8.6, 5.5 Hz, 1H), 4.24-4.14 (m, 1H), 3.66 (t,J = 4.7 Hz, 4H), 3.06-3.00 (m, 4H). 114 4-[3-(5,8- 448.1 1H NMR (400MHz, DMSO-d6) δ 9.36 difluoroquinolin-4-yl)- (d, J = 4.5 Hz, 1H),8.79-8.61 (m, 1H), 2-methyl-7-(4H-1,2,4- 8.12 (d, J = 4.5 Hz, 1H),7.88-7.76 (m, triazol-3- 2H), 7.57-7.48 (m, 1H), 6.85 (d, J =yl)benzimidazol-5- 2.2 Hz, 1H), 3.68 (t, J = 4.8 Hz, 4H), yl]morpholine3.11 (t, J = 4.9 Hz, 4H), 2.60 (s, 3H). 115 4-[3-(8-chloroquinolin-509.1 1H NMR (400 MHz, DMSO-d6) δ 9.22 4-yl)-2-pyridin-2-yl-7- (d, J =4.5 Hz, 1H), 8.95-8.88 (m, 1H), (4H-1,2,4-triazol-3- 8.30 (s, 1H), 7.99(dd, J = 7.5, 1.3 Hz, yl)benzimidazol-5- 1H), 7.97-7.90 (m, 2H), 7.85(d, J = yl]morpholine 4.6 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.44 (dd, J= 8.4, 7.5 Hz, 1H), 7.27- 7.20 (m, 2H), 6.52 (d, J = 2.3 Hz, 1H), 3.67(t, J = 4.7 Hz, 4H), 3.10-3.02 (m, 4H). 116 4-[3-(8-chloroquinolin-490.1 1H NMR (400 MHz, DMSO-d6) δ 9.34 4-yl)-2-(2- (d, J = 4.5 Hz, 1H),8.66-8.47 (m, 1H), methoxyethyl)-7-(4H- 8.12 (dd, J = 7.5, 1.2 Hz, 1H),8.04 (d, J = 1,2,4-triazol-3- 4.5 Hz, 1H), 7.78-7.73 (m, 1H), 7.62yl)benzimidazol-5- (dd, J = 8.5, 7.5 Hz, 1H), 7.34 (d, J = 8.4yl]morpholine Hz, 1H), 6.64 (d, J = 2.3 Hz, 1H), 3.69- 3.50 (m, 6H),3.13-3.00 (m, 6H), 2.98 (s, 3H). 117 4-[3-(8-chloroquinolin- 498.1 1HNMR (400 MHz, DMSO-d6) δ 9.29 4-yl)-2-(1H-pyrazol-5- (d, J = 4.5 Hz,1H), 8.33 (s, 1H), 8.04 yl)-7-(4H-1,2,4-triazol- (dd, J = 7.6, 1.3 Hz,1H), 7.95 (d, J = 4.6 3-yl)benzimidazol-5- Hz, 1H), 7.73 (d, J = 2.2 Hz,1H), 7.68- yl]morpholine 7.62 (m, 1H), 7.53-7.46 (m, 1H), 7.26 (s, 1H),7.22 (dd, J = 8.4, 1.2 Hz, 1H), 7.13 (s, 1H), 7.00 (s, 1H), 6.61 (d, J =2.2 Hz, 1H), 3.67 (t, J = 4.8 Hz, 4H), 3.09-3.03 (m, 4H). 1184-[3-(8-chloroquinolin- 515.1 1H NMR (400 MHz, DMSO-d6) δ 9.40-4-yl)-2-(1,2-thiazol-4- 9.33 (m, 2H), 8.42-8.38 (m, 1H),yl)-7-(4H-1,2,4-triazol- 8.34-8.27 (m, 1H), 8.11-8.04 (m,3-yl)benzimidazol-5- 2H), 7.78-7.75 (m, 1H), 7.58-7.52 yl]morpholine (m,1H), 7.28-7.22 (m, 1H), 6.65- 6.62 (m, 1H), 3.67 (t, J = 4.7 Hz, 4H),3.11-3.04 (m, 4H). 119 4-[3-(8-chloroquinolin- 515.1 1H NMR (400 MHz,DMSO-d6) δ 9.38- 4-yl)-2-(1,3-thiazol-5- 9.35 (m, 1H), 9.01-8.97 (m,1H), yl)-7-(4H-1,2,4-triazol- 8.37-8.30 (m, 1H), 8.29-8.20 (m,3-yl)benzimidazol-5- 1H), 8.13-8.07 (m, 2H), 7.72 (d, J = yl]morpholine2.3 Hz, 1H), 7.59-7.52 (m, 1H), 7.24- 7.18 (m, 1H), 6.65 (d, J = 2.3 Hz,1H), 3.67 (t, J = 4.8 Hz, 4H), 3.11-3.04 (m, 4H). 1204-[3-(8-chloroquinolin- 498.1 1H NMR (400 MHz, DMSO-d6) δ 9.354-yl)-2-(1H-pyrazol-4- (d, J = 4.5 Hz, 1H), 8.37 (s, 1H), 8.09yl)-7-(4H-1,2,4-triazol- (dd, J = 7.5, 1.2 Hz, 1H), 8.06 (d, J = 4.53-yl)benzimidazol-5- Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.66yl]morpholine (s, 2H), 7.57-7.51 (m, 1H), 7.25-7.21 (m, 1H), 6.64 (d, J= 2.3 Hz, 1H), 3.67 (t, J = 4.8 Hz, 4H), 3.08-3.03 (m, 4H). 1214-[3-(8-chloroquinolin- 512 1H NMR (400 MHz, DMSO-d6) δ 9.35 4-yl)-2-(1-(d, J = 4.5 Hz, 1H), 8.38 (s, 1H), 8.09 methylpyrazol-4-yl)-7- (dd, J =7.5, 1.2 Hz, 1H), 8.04 (d, J = 4.5 (4H-1,2,4-triazol-3- Hz, 1H),7.84-7.83 (m, 1H), 7.70 (d, J = yl)benzimidazol-5- 2.2 Hz, 1H),7.57-7.52 (m, 1H), 7.51- yl]morpholine 7.50 (m, 1H), 7.23 (dd, J = 8.6,1.2 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 3.73 (s, 3H), 3.66 (t, J = 4.8Hz, 4H), 3.07-3.01 (m, 4H). 122 4-[3-(5,8- 481.1 1H NMR (400 MHz,DMSO-d6) δ 9.43 dichloroquinolin-4-yl)- (d, J = 4.4 Hz, 1H), 8.77-8.60(m, 1H), 2-methyl-7-(4H-1,2,4- 8.17-8.12 (m, 2H), 7.84-7.76 (m,triazol-3- 2H), 6.83-6.79 (m, 1H), 3.67 (t, J = 4.9 yl)benzimidazol-5-Hz, 4H), 3.11 (t, J = 4.9 Hz, 4H), 2.56 (s, yl]morpholine 3H). 1234-[3-(5,8- 490.1 1H NMR (400 MHz, DMSO-d6) δ 9.25difluoroquinolin-4-yl)- (d, J = 4.5 Hz, 1H), 8.32-8.27 (m, 1H),2-(oxetan-3-yl)-7-(4H- 7.91 (d, J = 4.6 Hz, 1H), 7.82-7.73 (m,1,2,4-triazol-3- 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.44 (ddd,yl)benzimidazol-5- J = 12.3, 8.8, 3.8 Hz, 1H), 6.72 (d, J =yl]morpholine 2.3 Hz, 1H), 5.16-5.09 (m, 2H), 4.59 (ddd, J = 13.5, 8.6,5.5 Hz, 2H), 4.29- 4.19 (m, 1H), 3.71-3.63 (m, 4H), 3.05 (t, J = 4.9 Hz,4H). 124 4-[3-(5-fluoro-8- 444.2 1H NMR (400 MHz, DMSO-d6) δ 9.35methylquinolin-4-yl)-2- (d, J = 4.5 Hz, 1H), 8.81-8.69 (m, 1H),methyl-7-(4H-1,2,4- 8.03 (d, J = 4.5 Hz, 1H), 7.85-7.77 (m, triazol-3-2H), 7.42 (dd, J = 12.5, 8.1 Hz, 1H), yl)benzimidazol-5- 6.80 (d, J =2.2 Hz, 1H), 3.67 (t, J = 4.8 yl]morpholine Hz, 4H), 3.11 (t, J = 4.9Hz, 4H), 2.81 (s, 3H), 2.59 (s, 3H). 125 4-[3-(5,8- 462.2 1H NMR (400MHz, DMSO-d6) δ 9.35 difluoroquinolin-4-yl)- (d, J = 4.5 Hz, 1H),8.67-8.59 (m, 1H), 2-ethyl-7-(4H-1,2,4- 8.14 (d, J = 4.5 Hz, 1H),7.86-7.78 (m, triazol-3- 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.52 (ddd,yl)benzimidazol-5- J = 12.3, 8.7, 3.8 Hz, 1H), 6.81 (d, J =yl]morpholine 2.2 Hz, 1H), 3.67 (t, J = 4.8 Hz, 4H), 3.10 (t, J = 4.9Hz, 4H), 2.94-2.81 (m, 2H), 1.16 (t, J = 7.5 Hz, 3H). 1264-[3-(5-chloro-8- 464.1 1H NMR (400 MHz, DMSO-d6) δ 9.37fluoroquinolin-4-yl)-2- (d, J = 4.4 Hz, 1H), 8.78-8.67 (m, 1H),methyl-7-(4H-1,2,4- 8.14 (d, J = 4.4 Hz, 1H), 7.87-7.82 (m, triazol-3-2H), 7.83-7.79 (m, 1H), 6.81 (d, J = yl)benzimidazol-5- 2.2 Hz, 1H),3.70-3.65 (m, 4H), 3.15- yl]morpholine 3.09 (m, 4H), 2.58 (s, 3H). 1274-[3-(5- 412.1 1H NMR (400 MHz, DMSO-d6) δ 9.15- methylquinolin-4-yl)-7-9.08 (m, 1H), 9.07-8.99 (m, 1H), (4H-1,2,4-triazol-3- 8.50-8.45 (m, 1H),8.17-8.11 (m, yl)benzimidazol-5- 1H), 7.84-7.73 (m, 3H), 7.52-7.46yl]morpholine (m, 1H), 6.75-6.72 (m, 1H), 3.71- 3.66 (m, 4H), 3.13-3.08(m, 4H), 1.84 (s, 3H). 128 4-[3-(3-chloroquinolin- 446.1 1H NMR (400MHz, DMSO-d6) δ 9.38- 4-yl)-2-methyl-7-(4H- 9.29 (m, 1H), 8.67-8.56 (m,1H), 1,2,4-triazol-3- 8.38-8.27 (m, 1H), 8.02-7.92 (m,yl)benzimidazol-5- 1H), 7.79-7.68 (m, 2H), 7.54-7.44 yl]morpholine (m,1H), 6.82-6.72 (m, 1H), 3.74- 3.61 (m, 4H), 3.14-3.04 (m, 4H), 2.78-2.63 (m, 3H). 129 4-[3-(8-chloroquinolin- 460.1 1H NMR (400 MHz,DMSO-d6) δ 9.35 4-yl)-2-methyl-7-(5- (dd, J = 4.5, 0.6 Hz, 1H),8.16-8.10 (m, methyl-4H-1,2,4- 1H), 8.07 (d, J = 4.5 Hz, 1H), 7.77 (d, J= triazol-3- 2.2 Hz, 1H), 7.62 (ddd, J = 8.1, 7.4, yl)benzimidazol-5-0.6 Hz, 1H), 7.58-7.48 (m, 1H), 6.69 yl]morpholine (d, J = 2.2 Hz, 1H),3.64 (t, J = 4.8 Hz, 4H), 3.05 (t, J = 4.1 Hz, 4H), 2.60-2.56 (m, 2H),2.52 (d, J = 0.6 Hz, 2H). 130 4-[3-(8-fluoroquinolin- 444.1 1H NMR (400MHz, DMSO-d6) δ 9.32- 4-yl)-2-methyl-7-(5- 9.20 (m, 1H), 8.07 (d, J =4.5 Hz, 1H), methyl-4H-1,2,4- 7.83-7.71 (m, 2H), 7.64 (td, J = 8.1, 4.9triazol-3- Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 6.68 yl)benzimidazol-5-(d, J = 2.3 Hz, 1H), 3.64 (t, J = 4.8 Hz, yl]morpholine 4H), 3.11-2.96(m, 4H), 2.58 (s, 3H), 2.52 (d, J = 0.7 Hz, 3H). 131 4-[3-(5,7- 448.1 1HNMR (400 MHz, DMSO-d6) δ 9.25 difluoroquinolin-4-yl)- (d, J = 4.5 Hz,1H), 8.72 (s, 1H), 8.09 (d, 2-methyl-7-(4H-1,2,4- J = 4.5 Hz, 1H), 7.95(ddd, J = 11.3, 9.0, triazol-3- 2.7 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H),yl)benzimidazol-5- 7.36 (s, 1H), 6.71 (d, J = 2.2 Hz, 1H), yl]morpholine3.66 (s, 4H), 3.13-3.02 (m, 4H), 2.56 (s, 3H). 1324-[2-(azetidin-3-yl)-3- 487.2 1H NMR (400 MHz, DMSO-d6) δ 9.29(8-chloroquinolin-4- (dd, J = 4.5, 0.7 Hz, 1H), 9.10 (s, 1H),yl)-7-(4H-1,2,4-triazol- 8.70 (s, 1H), 8.25 (s, 1H), 8.10 (dt, J =3-yl)benzimidazol-5- 7.5, 1.0 Hz, 1H), 7.89 (dd, J = 4.6, 0.7yl]morpholine Hz, 1H), 7.74-7.69 (m, 1H), 7.62-7.53 (m, 1H), 7.26 (dt, J= 8.5, 1.0 Hz, 1H), 6.67-6.62 (m, 1H), 4.47 (d, J = 8.1 Hz, 1H), 4.21(s, 4H), 3.76 (p, J = 7.8 Hz, 1H), 3.65 (t, J = 4.8 Hz, 4H), 3.01 (q, J= 3.9 Hz, 4H). 133 4-[3-(8-chloroquinolin- 474.2 1H NMR (400 MHz,DMSO-d6) δ 9.50- 4-yl)-2-ethyl-7-(5- 9.25 (m, 1H), 8.11 (s, 2H), 7.73(s, 1H), methyl-4H-1,2,4- 7.61 (s, 1H), 7.54-7.39 (m, 1H), 6.65triazol-3- (d, J = 3.1 Hz, 1H), 3.63 (d, J = 4.9 Hz, yl)benzimidazol-5-4H), 3.12-2.95 (m, 4H), 2.86 (d, J = 7.6 yl]morpholine Hz, 2H),2.53-2.49 (m, 3H), 1.06 (s, 3H). 134 4-[3-(8-chloroquinolin- 446.2 1HNMR (400 MHz, DMSO-d6) δ 9.32- 4-yl)-7-(5-methyl-4H- 9.27 (m, 1H),9.07-8.95 (m, 1H), 1,2,4-triazol-3- 8.16-8.11 (m, 1H), 8.05-8.01 (m,yl)benzimidazol-5- 1H), 7.76-7.72 (m, 1H), 7.70-7.63 yl]morpholine (m,1H), 7.59-7.54 (m, 1H), 6.87- 6.83 (m, 1H), 3.72-3.66 (m, 4H), 3.14-3.04 (m, 4H), 2.48-2.47 (m, 3H). 135 4-[3-(8-chloroquinolin- 486.2 1HNMR (400 MHz, DMSO-d6) δ 9.40- 4-yl)-7-(5-cyclopropyl- 9.35 (m, 1H),8.18-8.13 (m, 1H), 4H-1,2,4-triazol-3-yl)- 8.11-8.06 (m, 1H), 7.75-7.69(m, 2-methylbenzimidazol- 1H), 7.68-7.61 (m, 1H), 7.59-7.535-yl]morpholine (m, 1H), 6.71-6.67 (m, 1H), 3.72- 3.59 (m, 4H),3.11-3.01 (m, 4H), 2.62- 2.56 (m, 3H), 2.26-2.16 (m, 1H), 1.17-1.05 (m,4H). 136 4-[3-(8-chloroquinolin- 514.2 1H NMR (400 MHz, DMSO-d6) δ 9.33-4-yl)-2-methyl-7-[5- 9.30 (m, 1H), 8.14-8.09 (m, 1H),(trifluoromethyl)-4H- 8.00 (d, J = 4.5 Hz, 1H), 7.65-7.57 (m,1,2,4-triazol-3- 2H), 7.30-7.25 (m, 1H), 6.71 (d, J = yl]benzimidazol-5-2.2 Hz, 1H), 3.65 (t, J = 4.7 Hz, 4H), yl]morpholine 3.07-3.00 (m, 4H),2.41 (s, 3H). 137 4-[3-(8-chloroquinolin- 474.2 1H NMR (400 MHz,DMSO-d6) δ 9.38 4-yl)-7-(5-ethyl-4H- (d, J = 4.5 Hz, 1H), 8.17-8.07 (m,2H), 1,2,4-triazol-3-yl)-2- 7.78 (d, J = 2.2 Hz, 1H), 7.68-7.54 (m,methylbenzimidazol-5- 2H), 6.71 (d, J = 2.2 Hz, 1H), 3.66 (t, J =yl]morpholine 4.8 Hz, 4H), 3.13-3.03 (m, 4H), 2.91 (q, J = 7.6 Hz, 2H),2.60 (s, 3H), 1.37 (t, J = 7.6 Hz, 3H). 138 4-[3-(8-chloroquinolin-488.2 1H NMR (400 MHz, DMSO-d6) δ 9.36 4-yl)-2-methyl-7-(5- (d, J = 4.5Hz, 1H), 8.16-8.12 (m, 1H), propan-2-yl-4H-1,2,4- 8.08 (d, J = 4.5 Hz,1H), 7.74 (d, J = 2.2 triazol-3- Hz, 1H), 7.67-7.61 (m, 1H), 7.52 (d, J= yl)benzimidazol-5- 8.5 Hz, 1H), 6.68 (d, J = 2.3 Hz, 1H),yl]morpholine 3.66 (t, J = 4.8 Hz, 4H), 3.29-3.19 (m, 1H), 3.12-2.99 (m,4H), 2.56 (s, 3H), 1.40 (d, J = 7.0 Hz, 6H). 139 4-[2-ethyl-3-(8- 444.21H NMR (400 MHz, DMSO-d6) δ 9.30 fluoroquinolin-4-yl)-7- (d, J = 4.5 Hz,1H), 8.65 (s, 1H), 8.10 (d, (4H-1,2,4-triazol-3- J = 4.5 Hz, 1H),7.82-7.75 (m, 2H), yl)benzimidazol-5- 7.69-7.61 (m, 1H), 7.32 (d, J =8.5 Hz, yl]morpholine 1H), 6.67 (d, J = 2.3 Hz, 1H), 3.66 (t, J = 4.7Hz, 4H), 3.11-3.02 (m, 4H), 2.86 (q, J = 7.5 Hz, 2H), 1.12 (t, J = 7.5Hz, 3H). 140 4-[3-(8-fluoroquinolin- 430.2 1H NMR (400 MHz, DMSO-d6) δ9.30 4-yl)-2-methyl-7-(4H- (d, J = 4.5 Hz, 1H), 8.79-8.65 (m, 1H),1,2,4-triazol-3- 8.07 (d, J = 4.5 Hz, 1H), 7.84-7.75 (m,yl)benzimidazol-5- 2H), 7.69-7.62 (m, 1H), 7.39 (d, J = yl]morpholine8.4 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 3.66 (t, J = 4.8 Hz, 4H),3.11-3.03 (m, 4H), 2.58 (s, 3H). 141 4-[3-(8-fluoroquinolin- 458.2 1HNMR (400 MHz, DMSO-d6) δ 9.29 4-yl)-2-propyl-7-(4H- (d, J = 4.4 Hz, 1H),8.62 (s, 1H), 8.09 (d, 1,2,4-triazol-3- J = 4.5 Hz, 1H), 7.83-7.73 (m,2H), yl)benzimidazol-5- 7.64 (td, J = 8.1, 5.0 Hz, 1H), 7.28 (d, J =yl]morpholine 8.5 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 3.66 (t, J = 4.8Hz, 4H), 3.12-2.98 (m, 4H), 2.91-2.74 (m, 2H), 1.66-1.46 (m, 2H), 0.78(t, J = 7.4 Hz, 3H). 142 4-[3-(7,8- 448.2 1H NMR (400 MHz, Methanol-d4)δ difluoroquinolin-4-yl)- 9.34 (d, J = 4.5 Hz, 1H), 8.75-8.59 (m,2-methyl-7-(4H-1,2,4- 1H), 8.06 (d, J = 4.5 Hz, 1H), 7.85- triazol-3-7.75 (m, 2H), 7.53-7.44 (m, 1H), 6.69 yl)benzimidazol-5- (d, J = 2.2 Hz,1H), 3.67 (t, J = 4.8 Hz, yl]morpholine 4H), 3.10-3.04 (m, 4H), 2.57 (s,3H). 143 4-[2-cyclopropyl-3- 474.2 1H NMR (400 MHz, Methanol-d4) δ(7,8-difluoroquinolin- 9.30 (d, J = 4.6 Hz, 1H), 8.38-8.30 (m,4-yl)-7-(4H-1,2,4- 1H), 8.01 (d, J = 4.5 Hz, 1H), 7.85- triazol-3- 7.74(m, 1H), 7.66-7.60 (m, 1H), 7.36- yl)benzimidazol-5- 7.26 (m, 1H),6.68-6.64 (m, 1H), yl]morpholine 3.67 (t, J = 4.7 Hz, 4H), 3.10-2.97 (m,4H), 1.70-1.60 (m, 1H), 1.49-1.30 (m, 2H), 1.02-0.80 (m, 2H). 1444-[2-cyclopropyl-3-(8- 456.2 1H NMR (400 MHz, Methanol-d4) δfluoroquinolin-4-yl)-7- 9.27 (d, J = 4.5 Hz, 1H), 8.41 (s, 1H),(4H-1,2,4-triazol-3- 8.03 (d, J = 4.5 Hz, 1H), 7.80-7.72 (m,yl)benzimidazol-5- 1H), 7.68-7.61 (m, 2H), 7.27-7.21 yl]morpholine (m,1H), 6.67 (d, J = 2.3 Hz, 1H), 3.67 (t, J = 4.8 Hz, 4H), 3.09-2.99 (m,4H), 1.71-1.61 (m, 1H), 1.48-1.30 (m, 2H), 1.02-0.82 (m, 2H). 1454-[3-(6,8- 448.2 1H NMR (400 MHz, DMSO-d6) δ 9.28difluoroquinolin-4-yl)- (d, J = 4.5 Hz, 1H), 8.79 (s, 1H), 8.12 (d,2-methyl-7-(4H-1,2,4- J = 4.5 Hz, 1H), 7.97 (ddd, J = 10.7, 9.0,triazol-3- 2.7 Hz, 1H), 7.86-7.81 (m, 1H), 7.48- yl)benzimidazol-5- 7.37(m, 1H), 6.74 (d, J = 2.3 Hz, 1H), yl]morpholine 3.68 (t, J = 4.8 Hz,4H), 3.14-3.07 (m, 4H), 2.61 (s, 3H). 146 4-[3-(6,8- 476.2 1H NMR (400MHz, DMSO-d6) δ 9.26 difluoroquinolin-4-yl)- (d, J = 4.5 Hz, 1H),8.72-8.61 (m, 1H), 2-propyl-7-(4H-1,2,4- 8.17-8.11 (m, 1H), 8.01-7.90(m, triazol-3- 1H), 7.84-7.76 (m, 1H), 7.34-7.20 yl)benzimidazol-5- (m,1H), 6.72-6.66 (m, 1H), 3.67 (t, J = yl]morpholine 4.8 Hz, 4H),3.10-3.05 (m, 4H), 2.95- 2.74 (m, 2H), 1.68-1.45 (m, 2H), 0.80 (t, J =7.3 Hz, 3H). 147 4-(2-methyl-4-(4H- 720.4 1,2,4-triazol-3-yl)-1-(2-(1-trityl-1H-pyrazol-4- yl)quinolin-4-yl)-1H- benzo[d]imidazol-6-yl)morpholine 148 tert-butyl 4-(4-(2- 596.4 methyl-6-morpholino-4-(4H-1,2,4-triazol-3- yl)-1H- benzo[d]imidazol-1- yl)quinolin-2-yl)piperazine-1- carboxylate 149 4-(1-(8-chloroquinolin- 450.1 1H NMR(400 MHz, DMSO-d6) δ 9.26 4-yl)-7-fluoro-4-(4H- (d, J = 4.5 Hz, 1H),8.73 (s, 1H), 8.28 (s, 1,2,4-triazol-3-yl)-1H- 1H), 8.12 (dd, J = 7.5,1.2 Hz, 1H), 8.07 benzo[d]imidazol-6- (d, J = 4.6 Hz, 1H), 7.75 (d, J =7.6 Hz, yl)morpholine 1H), 7.69-7.63 (m, 1H), 7.57-7.52 (m, 1H), 3.68(t, J = 4.6 Hz, 4H), 3.08- 2.93 (m, 4H). 150 4-(1-(8-chloro-5- 482.1 1HNMR (400 MHz, DMSO-d6) δ 9.35 fluoroquinolin-4-yl)-7- (d, J = 4.5 Hz,1H), 8.36 (s, 1H), 8.18- fluoro-2-methyl-4-(4H- 8.13 (m, 2H), 7.64 (d, J= 7.7 Hz, 1H), 1,2,4-triazol-3-yl)-1H- 7.55 (dd, J = 11.9, 8.5 Hz, 1H),3.69- benzo[d]imidazol-6- 3.63 (m, 4H), 3.05-2.90 (m, 4H), 2.43yl)morpholine (s, 3H). 151 4-(1-(5,8- 494.1 1H NMR (400 MHz, DMSO-d6) δ9.42 dichloroquinolin-4-yl)- (d, J = 4.4 Hz, 1H), 8.18-8.08 (m, 2H),2-methyl-4-(5-methyl- 7.81 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 2.24H-1,2,4-triazol-3-yl)- Hz, 1H), 6.79 (d, J = 2.2 Hz, 1H), 3.70-1H-benzo[d]imidazol- 3.49 (m, 4H), 3.08 (t, J = 4.9 Hz, 4H),6-yl)morpholine 2.56 (s, 3H), 2.51 (s, 3H). 152 4-(1-(5,8- 476.2 1H NMR(400 MHz, DMSO-d6) δ 9.35 difluoroquinolin-4-yl)- (d, J = 4.5 Hz, 1H),8.15 (d, J = 4.5 Hz, 2-ethyl-4-(5-methyl- 1H), 7.86-7.75 (m, 1H), 7.71(d, J = 4H-1,2,4-triazol-3-yl)- 2.3 Hz, 1H), 7.51 (ddd, J = 12.3, 8.8,3.7 1H-benzo[d]imidazol- Hz, 1H), 6.79 (d, J = 2.2 Hz, 1H), 3.656-yl)morpholine (t, J = 4.8 Hz, 4H), 3.07 (dd, J = 6.0, 3.8 Hz, 4H),2.90 (dd, J = 7.5, 3.4 Hz, 2H), 2.51 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H).153 4-(1-(3-fluoroquinolin- 430.2 1H NMR (400 MHz, DMSO-d6) δ 9.354-yl)-2-methyl-4-(4H- (d, J = 4.6 Hz, 1H), 8.53 (s, 1H), 8.29 (d,1,2,4-triazol-3-yl)-1H- J = 8.4 Hz, 1H), 7.91 (ddd, J = 8.5, 6.9,benzo[d]imidazol-6- 1.4 Hz, 1H), 7.71 (t, J = 7.6 Hz, 2H), yl)morpholine7.49 (d, J = 8.2 Hz, 1H), 6.79 (s, 1H), 3.65 (t, J = 4.8 Hz, 4H), 3.06(d, J = 3.3 Hz, 4H), 2.49 (s, 3H). 154 4-(1-(3-fluoroquinolin- 444.2 1HNMR (400 MHz, DMSO-d6) δ 9.35 4-yl)-2-methyl-4-(5- (d, J = 0.9 Hz, 1H),8.33-8.26 (m, 1H), methyl-4H-1,2,4- 7.91 (ddd, J = 8.5, 6.9, 1.3 Hz,1H), 7.76- triazol-3-yl)-1H- 7.65 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H),benzo[d]imidazol-6- 6.78 (d, J = 2.2 Hz, 1H), 3.64 (t, J = 4.8yl)morpholine Hz, 4H), 3.05 (q, J = 3.9 Hz, 4H), 2.49 (d, J = 1.9 Hz,6H). 155 4-(2-ethyl-6- 465.2 1H NMR (400 MHz, DMSO-d6) δ 9.34morpholino-4-(4H- (d, J = 0.5 Hz, 1H), 8.54 (s, 1H), 8.431,2,4-triazol-3-yl)-1H- (dd, J = 7.2, 1.3 Hz, 1H), 7.76-7.67 (m,benzo[d]imidazol-1- 2H), 7.60 (d, J = 8.4 Hz, 1H), 6.64 (d, J =yl)-3-methylquinoline- 2.3 Hz, 1H), 3.64 (t, J = 4.8 Hz, 4H),8-carbonitrile 3.05 (dd, J = 6.3, 3.8 Hz, 4H), 2.67 (d, J = 8.1 Hz, 2H),2.21 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H). 156 3-methyl-4-(2-methyl- 451.21H NMR (400 MHz, DMSO-d6) δ 9.35 6-morpholino-4-(4H- (d, J = 0.5 Hz,1H), 8.61 (s, 1H), 8.44 1,2,4-triazol-3-yl)-1H- (dd, J = 7.1, 1.4 Hz,1H), 7.87-7.60 (m, benzo[d]imidazol-1- 3H), 6.68 (d, J = 2.3 Hz, 1H),3.64 (t, J = yl)quinoline-8- 4.7 Hz, 4H), 3.06 (dd, J = 6.2, 3.7 Hz,carbonitrile 4H), 2.44 (s, 3H), 2.23 (s, 3H). 157 4-(1-(3,8- 494.1 1HNMR (400 MHz, DMSO-d6) δ 9.42 dichloroquinolin-4-yl)- (s, 1H), 8.14 (dd,J = 7.6, 1.2 Hz, 1H), 2-methyl-4-(5-methyl- 7.71-7.62 (m, 2H), 7.38 (d,J = 8.5 Hz, 4H-1,2,4-triazol-3-yl)- 1H), 6.76 (d, J = 2.3 Hz, 1H), 3.72-1H-benzo[d]imidazol- 3.58 (m, 4H), 3.04 (dd, J = 6.1, 3.8 Hz,6-yl)morpholine 4H), 2.48 (s, 3H), 2.44 (s, 3H). 158 tert-butyl 4-(4-(6-morpholino-4-(4H- 1,2,4-triazol-3-yl)-1H- benzo[d]imidazol-1-yl)quinolin-2- yl)piperazine-1- carboxylate 159 4-(4-(5-methyl-4H-1,2,4-triazol-3-yl)-1-(2- (1-trityl-1H-pyrazol-3- yl)quinolin-4-yl)-1H-benzo[d]imidazol-6- yl)morpholine 384 4-(4-(4H-1,2,4-triazol-3-yl)-1-(2-(1-trityl-1H- pyrazol-3-yl)quinolin- 4-yl)-1H-benzo[d]imidazol-6- yl)morpholine 385 4-(4-(5-methyl-4H-1,2,4-triazol-3-yl)-1-(2- (1-trityl-1H-pyrazol-4- yl)quinolin-4-yl)-1H-benzo[d]imidazol-6- yl)morpholine 386 4-(4-(4H-1,2,4-triazol-3-yl)-1-(2-(1-trityl-1H- pyrazol-4-yl)quinolin- 4-yl)-1H-benzo[d]imidazol-6- yl)morpholine 391 4-(1-(3-(4H-1,2,4- 493.2 1H NMR(400 MHz, DMSO-d6) δ 9.91 triazol-3-yl)quinolin-4- (s, 1H), 8.72 (s,1H), 8.60 (s, 1H), 8.35- yl)-2-ethyl-4-(4H- 8.28 (m, 1H), 7.96 (ddd, J =8.4, 6.9, 1.4 1,2,4-triazol-3-yl)-1H- Hz, 1H), 7.77-7.65 (m, 2H), 7.57(s, benzo[d]imidazol-6- 1H), 6.57 (d, J = 2.2 Hz, 1H), 3.81-yl)morpholine 3.43 (m, 4H), 2.98 (t, J = 4.9 Hz, 4H), 2.84-2.57 (m, 2H),0.95 (t, J = 7.5 Hz, 3H). 392 4-(1-(3-(4H-1,2,4- 479.2 1H NMR (400 MHz,DMSO-d6) δ 9.91 triazol-3-yl)quinolin-4- (s, 1H), 8.83 (s, 1H), 8.60 (s,1H), 8.32 yl)-2-methyl-4-(4H- (dt, J = 8.5, 0.9 Hz, 1H), 7.97 (ddd, J =1,2,4-triazol-3-yl)-1H- 8.4, 6.8, 1.5 Hz, 1H), 7.89-7.53 (m,benzo[d]imidazol-6- 4H), 6.60 (d, J = 2.2 Hz, 1H), 3.59 (t, J =yl)morpholine 4.8 Hz, 4H), 2.99 (t, J = 5.0 Hz, 4H), 2.49 (s, 3H).

Step 5a:4-(2-methyl-1-(2-methylquinolin-4-yl)-4-(1H-tetrazol-5-yl)-1H-benzo[d]imidazol-6-yl)morpholine

To a suspension of ammonium chloride (193 mg, 3.6 mmol) indichloroethane (2 mL) at 0° C. under N₂ was added trimethylaluminum (1.8mL of a 2.0M heptane solution, 3.6 mmol). The mixture was stirred at 0°C. for 5 minutes, then at ambient temperature for 20 minutes. Thereaction was cooled back to 0° C., and a suspension of methyl2-methyl-1-(2-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate(300 mg, 0.72 mmol) in dichloroethane (1 mL) was added. The reaction wasallowed to warm to ambient temperature and stir for 3 days. Afterheating to 60° C. for 3 hours the reaction was allowed to cool, thentreated with aq. citric acid. The product was extracted 3× intodichloromethane and was purified on silica (0-100% EtOAc in DCM) to give2-methyl-1-(2-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carbonitrile.2-Methyl-1-(2-methylquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazole-4-carbonitrile(50 mg, 0.13 mmol) was combined with sodium azide (85 mg, 1.3 mmol) andammonium chloride (70 mg, 1.3 mmol) in DMF (1 mL) and heated in amicrowave at 100° C. for 14 hours. The crude reaction was purified bypreparatory LC to provide4-(2-methyl-1-(2-methylquinolin-4-yl)-4-(1H-tetrazol-5-yl)-1H-benzo[d]imidazol-6-yl)morpholine(Compound 160). 1H NMR (400 MHz, DMSO-d6) δ 8.21-8.14 (m, 1H), 7.88(ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J=2.2 Hz, 1H),7.58 (ddd, J=8.2, 6.9, 1.2 Hz, 1H), 7.31 (d, J=8.2 Hz, 1H), 6.71 (d,J=2.2 Hz, 1H), 3.67 (t, J=4.8 Hz, 4H), 3.14-2.99 (m, 4H), 2.82 (s, 3H),2.45 (s, 3H). ES/MS m/z=427.2 (M+H)⁺.

The compounds listed in the table below were prepared in a mannersimilar to that described above using appropriate intermediates andchemistry.

Compound Compound Name MS NMR 161 4-(1-(8- 447.1 1H NMR (400 MHz,DMSO-d6) δ chloroquinolin-4- 9.34 (d, J = 4.5 Hz, 1H), 8.12 (dd, J =7.6, yl)-2-methyl-4- 1.2 Hz, 1H), 8.02 (d, J = 4.5 Hz, 1H),(1H-tetrazol-5-yl)- 7.70 (d, J = 2.2 Hz, 1H), 7.62 (dd, J = 8.5, 1H- 7.5Hz, 1H), 7.36 (dd, J = 8.5, 1.2 Hz, 1H), benzo[d]imidazol- 6.76 (d, J =2.2 Hz, 1H), 3.67 (t, J = 4.7 Hz, 4H), 6-yl)morpholine 3.07 (q, J = 4.1Hz, 4H), 2.45 (s, 3H).

Step 5b:4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(1,3,4-oxadiazol-2-yl)-1H-benzo[d]imidazol-6-yl)morpholine

A solution of methyl1-(8-chloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate(210 mg, 0.48 mmol) and hydrazine hydrate (0.46 mL, 9.6 mmol) in ethanolwas refluxed for 2 h. Upon cooling, the reaction mixture wasconcentrated. Ethyl acetate and water were added followed by twoextractions of the aqueous phase with ethyl acetate. The combinedorganic phases were dried over MgSO4, filtrated and concentrated underreduce pressure to afford1-(8-chloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carbohydrazide(ES/MS m/z=437.1 (M+H)⁺) which was dissolved in trimethylorthoformate(2.6 mL) and trifluoroacetic acid (0.5 mL) and heated to 100° C. for 45minutes. After cooling and concentration under reduced pressure, theresultant was purified by HPLC eluting with 5-95% water/acetonitrile(0.1% v/v trifluoroacetic acid). The appropriate fractions were pooledand lyophilized to afford4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(1,3,4-oxadiazol-2-yl)-1H-benzo[d]imidazol-6-yl)morpholineas a 2,2,2-trifluoroacetic acid salt (Compound 162). 1H NMR (400 MHz,DMSO-d6) δ 9.50 (s, 1H), 9.31 (d, J=4.5 Hz, 1H), 8.10 (dd, J=7.5, 1.2Hz, 1H), 7.98 (d, J=4.5 Hz, 1H), 7.63-7.56 (m, 2H), 7.32 (dd, J=8.5, 1.2Hz, 1H), 6.77 (d, J=2.2 Hz, 1H), 3.64 (t, J=4.8 Hz, 4H), 3.04 (q, J=4.3Hz, 4H), 2.39 (s, 3H). ES/MS m/z=447.1 (M+H)⁺.

Step 5c:5-(1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazol-4-yl)-1,3,4-oxadiazol-2-amine

1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carbohydrazidewas prepared in a manner similar to1-(8-chloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carbohydrazide.A mixture of1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carbohydrazide(50 mg, 0.119 mmol), sodium bicarbonate (15 mg, 0.178 mmol) and BrCN(14.5 mg, 0.137 mmol) was stirred at room temperature for 4 hours. Afterconcentration under reduced pressure, the resultant was purified by HPLCeluting with 5-95% water/acetonitrile (0.1% v/v trifluoroacetic acid).The appropriate fractions were pooled and lyophilized to afford5-(1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazol-4-yl)-1,3,4-oxadiazol-2-amineas a 2,2,2-trifluoroacetic acid salt (Compound 163). 1H NMR (400 MHz,DMSO-d6) δ 9.23 (d, J=4.6 Hz, 1H), 8.09-8.00 (m, 1H), 7.88 (d, J=4.6 Hz,1H), 7.63-7.45 (m, 5H), 7.39 (d, J=2.2 Hz, 1H), 6.66 (s, 1H), 3.63 (t,J=4.8 Hz, 4H), 3.06-2.98 (m, 4H), 2.44 (s, 3H). ES/MS m/z=446.2 (M+H)⁺.

Step 5d:5-(1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazol-4-yl)-1,3,4-oxadiazole-2(3H)-thione

1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carbohydrazidewas prepared in a manner similar to1-(8-chloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carbohydrazide.A mixture of1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carbohydrazide(50 mg, 0.119 mmol), potassium hydroxide (13.3 mg, 0.238 mmol) and CS₂(14.3 □L, 0.238 mmol) was refluxed for 20 hours. After concentrationunder reduced pressure, the resultant was purified by HPLC eluting with5-95% water/acetonitrile (0.1% v/v trifluoroacetic acid). Theappropriate fractions were pooled and lyophilized to afford5-(1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazol-4-yl)-1,3,4-oxadiazole-2(3H)-thioneas a 2,2,2-trifluoroacetic acid salt (Compound 164). H NMR (400 MHz,DMSO-d6) δ 9.21 (d, J=4.6 Hz, 1H), 8.02 (dd, J=10.1, 2.6 Hz, 1H), 7.83(d, J=4.7 Hz, 1H), 7.57 (td, J=8.9, 2.7 Hz, 1H), 7.43-7.35 (m, 2H), 6.71(d, J=2.2 Hz, 1H), 3.63 (t, J=4.7 Hz, 4H), 3.08-2.94 (m, 4H), 2.35 (d,J=1.3 Hz, 3H). ES/MS m/z=463.2 (M+H)⁺.

Step 5e:5-(1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazol-4-yl)-1,3,4-thiadiazol-2-amine

1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carbohydrazidewas prepared in a manner similar to1-(8-chloroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carbohydrazide.A mixture of1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carbohydrazide(100 mg, 0.238 mmol) and trimethylsilyl isothiocyanate (33 □L, 0.238mmol) in ethanol (2.3 mL) was refluxed for 4 h, and then the reactionmixture was concentrated. After adding conc. H₂SO₄ (2.3 mL), thesolution was stirred at 30° C. for 6 h. The mixture was slowlyneutralized by adding potassium carbonate. The aqueous phase wasextracted twice with dichloromethane. After concentration under reducedpressure, the resultant was purified by HPLC eluting with 5-95%water/acetonitrile (0.1% v/v trifluoroacetic acid). The appropriatefractions were pooled and lyophilized to5-(1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazol-4-yl)-1,3,4-thiadiazol-2-amineas a 2,2,2-trifluoroacetic acid salt (Compound 165). 1H NMR (400 MHz,DMSO-d6) δ 9.22-9.19 (m, 1H), 8.03-7.98 (m, 1H), 7.85-7.82 (m, 1H),7.73-7.51 (m, 4H), 7.48-7.41 (m, 1H), 6.55-6.52 (m, 1H), 3.68-3.60 (m,4H), 3.05-2.95 (m, 4H), 2.35 (s, 3H). ES/MS m/z=462.2 (M+H)⁺.

Step 5f:5-(1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazol-4-yl)-1,3,4-oxadiazol-2(3H)-one

1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carbohydrazidewas prepared in a manner similar to1-(8-chloroquinolin-4-yl)-2-methyl-6-morpholino-H-benzo[d]imidazole-4-carbohydrazide.A mixture of1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carbohydrazide(50 mg, 0.119 mmol) and carbonyl diimidazole (21 mg, 0.131 mmol) in THF(2.0 mL) was stirred at room temperature for 16 h. After concentrationunder reduced pressure, the resultant was purified by HPLC eluting with5-95% water/acetonitrile (0.1% v/v trifluoroacetic acid). Theappropriate fractions were pooled and lyophilized to afford5-(1-(7-fluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazol-4-yl)-1,3,4-oxadiazol-2(3H)-oneas a 2,2,2-trifluoroacetic acid salt (Compound 166). 1H NMR (400 MHz,DMSO-d6) δ 12.75 (s, 1H), 9.20 (d, J=4.6 Hz, 1H), 8.02 (dd, J=10.1, 2.6Hz, 1H), 7.83 (d, J=4.6 Hz, 1H), 7.57 (td, J=8.8, 2.7 Hz, 1H), 7.42 (dd,J=9.2, 6.0 Hz, 1H), 7.35 (d, J=2.2 Hz, 1H), 6.65 (d, J=2.2 Hz, 1H), 3.62(t, J=4.8 Hz, 4H), 3.08-2.93 (m, 4H), 2.36 (s, 3H). ES/MS m/z=447.2(M+H)⁺.

Step 5g:4-(1-(2-(1H-pyrazol-4-yl)quinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-6-yl)morpholine

Trifluoroacetic acid (0.50 mL, 6.53 mmol) was added to4-(2-methyl-4-(4H-1,2,4-triazol-3-yl)-1-(2-(1-trityl-1H-pyrazol-4-yl)quinolin-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine(180 mg, 0.25 mmol) in DCM (6 mL). The reaction mixture was stirred for2 hours at ambient temperature. The resultant was purified by HPLCeluting with 5-95% water/acetonitrile (0.1% v/v trifluoroacetic acid).The appropriate fractions were pooled and lyophilized to afford4-(1-(2-(1H-pyrazol-4-yl)quinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-6-yl)morpholine2,2,2-trifluoroacetate (Compound 167). ¹H NMR (400 MHz, DMSO-d6) δ 8.81(s, 1H), 8.40 (s, 2H), 8.35 (s, 1H), 8.23-8.13 (m, 1H), 7.93-7.83 (m,2H), 7.60-7.48 (m, 2H), 6.79-6.73 (m, 1H), 3.65 (t, J=4.8 Hz, 4H),3.13-3.04 (m, 4H), 2.66 (s, 3H). ES/MS m/z=478.20 (M+H)⁺. The compoundslisted in the table below were prepared in a manner similar to thatdescribed above using appropriate intermediates and chemistry known tothose skilled in the art.

Compound name MS NMR 380 4-(1-(2-(1H-pyrazol-4- 478.2 1H NMR (400 MHz,DMSO-d6) yl)quinolin-4-yl)-4-(5- δ 9.23 (s, 1H), 8.44 (s, 2H),methyl-4H-1,2,4-triazol-3- 8.30 (s, 1H), 8.18-8.12 (m, 1H),yl)-1H-benzo[d]imidazol-6- 7.85 (ddd, J = 8.4, 6.8, 1.5 Hz,yl)morpholine 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.55 (ddd, J = 8.1, 6.8,1.2 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 2.3 Hz, 1H), 3.66(t, J = 4.8 Hz, 4H), 3.08 (d, J = 5.2 Hz, 5H), 2.49 (s, 3H). 3814-(1-(2-(1H-pyrazol-4- 464.2 1H NMR (400 MHz, DMSO-d6)yl)quinolin-4-yl)-4-(4H- δ 9.19 (s, 1H), 8.50 (s, 1H),1,2,4-triazol-3-yl)-1H- 8.45 (s, 2H), 8.30 (s, 1H), 8.15 (ddd,benzo[d]imidazol-6- J = 8.5, 1.2, 0.6 Hz, 1H), yl)morpholine 7.85 (ddd,J = 8.4, 6.8, 1.4 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.55 (ddd, J = 8.1,6.8, 1.2 Hz, 1H), 7.49-7.44 (m, 1H), 6.85 (d, J = 2.3 Hz, 1H), 3.67 (t,J = 4.8 Hz, 4H), 3.15-3.02 (m, 4H). 382 4-(1-(2-(1H-pyrazol-3- 478.2 1HNMR (400 MHz, DMSO-d6) yl)quinolin-4-yl)-4-(5- δ 8.42 (s, 1H), 8.23 (d,J = 8.6 Hz, methyl-4H-1,2,4-triazol-3- 1H), 7.94-7.86 (m, 1H),yl)-1H-benzo[d]imidazol-6- 7.77 (d, J = 2.2 Hz, 1H), yl)morpholine 7.61(ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.12 (d, J =2.3 Hz, 1H), 6.84 (d, J = 2.2 Hz, 1H), 3.66 (t, J = 4.8 Hz, 5H), 3.08(d, J = 7.2 Hz, 5H), 2.49 (s, 3H). 383 4-(1-(2-(1H-pyrazol-3- 464.2 1HNMR (400 MHz, DMSO-d6) yl)quinolin-4-yl)-4-(4H- δ 9.20 (s, 1H), 8.50 (s,1H), 1,2,4-triazol-3-yl)-1H- 8.42 (s, 1H), 8.23 (ddd, J = 8.5, 1.1,benzo[d]imidazol-6- 0.6 Hz, 1H), 7.90 (ddd, J = 8.4, yl)morpholine 6.9,1.4 Hz, 2H), 7.81 (d, J = 2.2 Hz, 1H), 7.61 (ddd, J = 8.2, 6.8, 1.2 Hz,1H), 7.51 (ddd, J = 8.4, 1.5, 0.7 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H),6.85 (d, J = 2.3 Hz, 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.08 (d, J = 5.1 Hz,4H).

Step 5h:4-(2-methyl-1-(2-(piperazin-1-yl)quinolin-4-yl)-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-6-yl)morpholine2,2,2-trifluoroacetate

To a solution of tert-butyl4-(4-(2-methyl-6-morpholino-4-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)quinolin-2-yl)piperazine-1-carboxylate(319 mg, 0.54 mmol) in DCM (3.0 mL) was added TFA (0.8 mL). Afterconcentration under reduced pressure, the resultant was purified by HPLCeluting with 5-95% water/acetonitrile (0.1% v/v trifluoroacetic acid).The appropriate fractions were pooled and lyophilized to afford theparent compound as a 2,2,2-trifluoroacetic acid salt. ES/MS m/z=482.2(M+H)⁺. (Compound 168). ¹H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 2H), 8.71(s, 1H), 7.87-7.67 (m, 4H), 7.34-7.21 (m, 2H), 6.71-6.64 (m, 1H),4.03-3.90 (m, 4H), 3.72-3.64 (m, 4H), 3.31-3.26 (m, 4H), 3.14-3.04 (m,4H), 2.59 (s, 3H). ES/MS m/z 496.30 (M+H)⁺.

The compounds listed in the table below were prepared in a mannersimilar to that described above using appropriate intermediates andchemistry known to those skilled in the art.

Compound name MS NMR 169 4-(2-methyl-4-(5-methyl-4H- 510.3 1H NMR (400MHz, DMSO-d6) 1,2,4-triazol-3-yl)-1-(2- δ 8.87 (s, 1H), 7.82 (dt, J =8.6, (piperazin-1-yl)quinolin-4- 0.9 Hz, 1H), 7.76 (s, 1H),yl)-1H-benzo[d]imidazol-6- 7.73 (dddd, J = 8.4, 6.7, 1.4, 0.0 Hz,yl)morpholine 1H), 7.30 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.25-7.19 (m,1H), 6.63 (d, J = 1.9 Hz, 1H), 3.96 (dd, J = 6.2, 4.0 Hz, 4H), 3.67 (t,J = 4.8 Hz, 4H), 3.33-3.24 (m, 4H), 3.07 (q, J = 4.6 Hz, 4H), 2.56 (s,3H), 2.51 (s, 3H). 379 4-(1-(2-(piperazin-1- 482.3 1H NMR (400 MHz,DMSO-d6) yl)quinolin-4-yl)-4-(4H- δ 8.89 (s, 3H), 8.40 (s, 1H),1,2,4-triazol-3-yl)-1H- 7.82-7.75 (m, 2H), 7.74-7.67 (m,benzo[d]imidazol-6- 2H), 7.34-7.25 (m, 2H), yl)morpholine 6.79 (d, J =2.3 Hz, 1H), 3.97 (s, 4H), 3.69 (t, J = 4.8 Hz, 4H), 3.25 (s, 4H), 3.08(d, J = 5.1 Hz, 4H).

Step 5i:5-(1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazol-4-yl)-4H-1,2,4-triazol-3-amine

Anhydrous hydrazine (0.36 mL, 11.4 mmol) was added to a suspension ofmethyl1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carboxylate(500 mg, 1.14 mmol) in MeOH (4 mL) and heated to 65 C. After severalhours, the reaction was cooled and filtered. The yellow solid was washedwith MeOH and dried to give1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carbohydrazide.1-(5,8-difluoroquinolin-4-yl)-2-methyl-6-morpholino-1H-benzo[d]imidazole-4-carbohydrazide(99 mg, 0.226 mmol) and cyanamide (80 mg, 1.90 mmol) were combined inDMF (0.5 mL) and heated to 120° C. for 4 days. The mixture was purifiedby HPLC eluting with 5-95% water/acetonitrile (0.1% v/v trifluoroaceticacid) to give the title compound (Compound 393). 1H NMR (400 MHz,DMSO-d6) δ 9.33 (d, J=4.5 Hz, 1H), 8.05 (d, J=4.5 Hz, 1H), 7.81 (ddd,J=10.0, 9.0, 4.2 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 7.54-7.44 (m, 1H),6.83 (d, J=2.3 Hz, 1H), 3.70-3.63 (m, 4H), 3.09-3.02 (m, 4H), 2.48 (s,3H). ES/MS m/z=463.2 (M+H)⁺.

Step 6:4-(4-(5-chloro-4H-1,2,4-triazol-3-yl)-1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine

[1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II), complexwith dichloromethane (50.29 mg, 0.06 mmol) was added to a mixture of4-(4-bromo-1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine(293 mg, 0.62 mmol), Bis-(Pinacolato) Diboron (187.67 mg, 0.74 mmol),and potassium acetate (181.33 mg, 1.85 mmol) in dioxane (1.2 mL). Thereaction mixture was degassed and stirred at 125° C. for 5 hours. Theresultant was filtered through a pad of celite and washed with ethylacetate (25 mL). The filtrate was concentrated to afford4-(1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-6-yl)morpholine,which was dissolved in THF (10 mL) and water (2 mL) with3,5-dichloro-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole (205.16 mg,0.92 mmol) and tripotassium phosphate (39 mg, 2 mmol).

Tetrakis(triphenylphosphine)palladium(0) (71 mg, 0.06 mmol) was addedand the reagents were stirred at 90° C. for 16 hours, after which timethe reaction mixture was cooled to ambient temperature and partitionedbetween ethyl acetate (50 mL) and water (50 mL). The aqueous layer wasextracted 3 times with ethyl acetate. The combined organic phases weredried with sodium sulfate and filtered. The resultant residue waspurified on silica gel with 0 to 100% ethyl acetate in hexanes to afford4-(4-(5-chloro-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)-1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholinewhich was dissolved in DCM (2 mL). Trifluoroacetic acid (2 mL) was addedand the reaction mixture was stirred at 40° C. for 2 hour, after whichthe reaction was cooled to ambient temperature. The resultant waspurified by HPLC eluting with 5-95% water/acetonitrile (0.1% v/vtrifluoroacetic acid). The appropriate fractions were pooled andlyophilized to afford4-(4-(5-chloro-4H-1,2,4-triazol-3-yl)-1-(8-chloro-5-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine(Compound 170). ¹H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J=4.5 Hz, 1H),8.15-8.07 (m, 1H), 8.00 (d, J=4.5 Hz, 1H), 7.53-7.43 (m, 2H), 6.79 (d,J=2.2 Hz, 1H), 3.67-3.61 (m, 4H), 3.04 (t, J=4.9 Hz, 4H), 2.39 (s, 3H).ES/MS m/z=498.1 (M+H)⁺.

The compounds listed in the table below were prepared in a mannersimilar to that described above using appropriate intermediates andchemistry known to those skilled in the art.

Compound name MS NMR 171 4-(4-(5-chloro-4H-1,2,4- 498.1 1H NMR (400 MHz,DMSO-d6) δ triazol-3-yl)-1-(8- 9.36 (d, J = 4.5 Hz, 1H), 7.99 (d, J =4.6 Hz, chloro-7-fluoroquinolin- 1H), 7.75 (t, J = 9.1 Hz,4-yl)-2-methyl-1H- 1H), 7.59-7.54 (m, 1H), benzo[d]imidazol-6- 7.44-7.36(m, 1H), 6.73-6.65 (m, 1H), yl)morpholine 3.66 (t, J = 4.8 Hz, 4H),3.05-3.01 (m, 4H), 2.43 (s, 3H). 172 4-(4-(5-chloro-4H-1,2,4- 512.1 1HNMR (400 MHz, DMSO-d6) δ triazol-3-yl)-1-(8- 9.35 (d, J = 4.5 Hz, 1H),8.00 (d, J = 4.6 Hz, chloro-7-fluoroquinolin- 1H), 7.74 (t, J = 9.1 Hz,4-yl)-2-ethyl-1H- 1H), 7.57-7.52 (m, 1H), benzo[d]imidazol-6- 7.38-7.30(m, 1H), 6.69-6.65 (m, 1H), yl)morpholine 3.65 (t, J = 4.8 Hz, 4H),3.06-2.98 (m, 4H), 2.77-2.57 (m, 2H), 1.21 (t, J = 7.5 Hz, 3H). 1734-(4-(5-chloro-4H-1,2,4- 524.1 1H NMR (400 MHz, DMSO-d6) δtriazol-3-yl)-1-(8- 9.35 (d, J = 4.6 Hz, 1H), 8.00 (d, J = 4.6 Hz,chloro-7-fluoroquinolin- 1H), 7.79-7.72 (m, 1H), 4-yl)-2-cyclopropyl-1H-7.53-7.51 (m, 1H), 7.45-7.37 (m, benzo[d]imidazol-6- 1H), 6.71-6.68 (m,1H), 3.65 (t, J = 4.8 Hz, yl)morpholine 4H), 3.05-2.97 (m, 4H),1.63-1.53 (m, 1H), 1.52-1.42 (m, 1H), 1.43-1.33 (m, 1H), 0.98-0.89 (m,1H), 0.87-0.77 (m, 1H),. 174 4-(4-(5-chloro-4H-1,2,4- 524.1 1H NMR (400MHz, DMSO-d6) δ triazol-3-yl)-1-(8- 9.36 (d, J = 4.5 Hz, 1H),chloro-5-fluoroquinolin- 8.15-8.09 (m, 1H), 8.03 (d, J = 4.5 Hz, 1H),4-yl)-2-cyclopropyl-1H- 7.53-7.45 (m, 2H), 6.81-6.78 (m,benzo[d]imidazol-6- 1H), 3.66 (t, J = 4.8 Hz, 4H), yl)morpholine 3.04(t, J = 4.8 Hz, 4H), 1.66-1.55 (m, 1H), 1.48-1.38 (m, 1H), 1.33-1.25 (m,1H), 0.93-0.78 (m, 2H). 175 4-[3-(8-chloroquinolin- 445.1 1H NMR (400MHz, DMSO-d6) δ 4-yl)-7-(1H-imidazol-2- 9.33 (d, J = 4.6 Hz, 1H), yl)-2-8.16-8.09 (m, 1H), 7.99 (d, J = 4.5 Hz, 1H), methylbenzimidazol-5- 7.87(d, J = 0.6 Hz, 2H), 7.72 (d, J = 2.1 Hz, yl]morpholine 1H), 7.62 (dd, J= 8.4, 7.6 Hz, 1H), 7.26-7.18 (m, 1H), 6.78 (d, J = 2.1 Hz, 1H),3.70-3.60 (m, 4H), 3.06 (dd, J = 6.6, 3.7 Hz, 4H), 2.44-2.39 (m, 3H).176 4-[3-(8-chloroquinolin- 459.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7-(4- 9.31 (d, J = 4.5 Hz, 1H), 9.16 (s,methyl-1H-imidazol-2- 1H), 8.12 (dd, J = 7.6, 1.2 Hz, 1H),yl)benzimidazol-5- 7.95 (d, J = 4.5 Hz, 1H), yl]morpholine 7.67-7.59 (m,1H), 7.21 (dd, J = 8.4, 1.2 Hz, 1H), 7.10 (d, J = 2.2 Hz, 1H), 6.57 (d,J = 2.2 Hz, 1H), 3.65 (t, J = 4.7 Hz, 4H), 3.07-2.95 (m, 4H), 2.54 (s,3H), 2.32 (s, 3H). 177 4-[3-(8-chloroquinolin- 459.1 1H NMR (400 MHz,DMSO-d6) δ 4-yl)-2-methyl-7-(4- 9.32 (d, J = 4.5, 0.7 Hz, 1H),methyl-1H-imidazol-5- 9.16 (s, 1H), 8.12 (d, J = 7.5, 1.0 Hz,yl)benzimidazol-5- 1H), 7.95 (d, J = 4.6, 0.7 Hz, 1H), yl]morpholine7.63 (dd, J = 8.3, 7.5 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.10 (d, J =2.2 Hz, 1H), 6.60-6.54 (m, 1H), 3.65 (t, J = 4.7 Hz, 4H), 3.01 (q, J =4.1 Hz, 4H), 2.53 (s, 3H), 2.33 (s, 3H). 178 4-[3-(8-chloroquinolin-480.1 1H NMR (400 MHz, DMSO-d6) δ 4-yl)-7-(5-chloro-4H- 9.30 (d, J = 4.5Hz, 1H), 8.10 (d, J = 7.5 Hz, 1,2,4-triazol-3-yl)-2- 1H), 7.99 (d, J =4.5 Hz, methylbenzimidazol-5- 1H), 7.59 (m, 2H), 7.30 (s, 1H),yl]morpholine 6.67 (s, 1H), 3.63 (m, 4H), 3.02 (bs, 4H), 2.41 (s, 3H).179 4-[7-(5-chloro-4H-1,2,4- 496.2 1H NMR (400 MHz, DMSO-d6) δtriazol-3-yl)-3-(5,8- 9.27 (d, J = 4.6 Hz, 1H), 8.00 (d, J = 4.5 Hz,difluoroquinolin-4-yl)- 1H), 7.82-7.71 (m, 1H), 2-ethylbenzimidazol-5-7.54-7.40 (m, 2H), 6.76 (d, J = 2.0 Hz, yl]morpholine 1H), 3.70-3.58 (m,4H), 3.09-3.00 (m, 4H), 2.73-2.61 (m, 2H), 1.20 (t, J = 7.9, 7.1 Hz,3H). 180 4-[7-(5-chloro-4H-1,2,4- 482.2 1H NMR (400 MHz, DMSO-d6) δtriazol-3-yl)-3-(5,8- 9.29 (d, J = 4.5 Hz, 1H), 8.00 (d, J = 4.4 Hz,difluoroquinolin-4-yl)- 1H), 7.78 (td, J = 9.4, 4.2 Hz,2-methylbenzimidazol- 1H), 7.57-7.41 (m, 2H), 5-yl]morpholine 6.80 (d, J= 2.1 Hz, 1H), 3.75-3.55 (m, 4H), 3.05 (t, J = 4.8 Hz, 4H), 2.42 (s,3H). 181 4-[7-(5-chloro-4H-1,2,4- 508.2 1H NMR (400 MHz, DMSO-d6) δtriazol-3-yl)-2- 9.27 (d, J = 4.5 Hz, 1H), 8.00 (d, J = 4.5 Hz,cyclopropyl-3-(5,8- 1H), 7.76 (ddd, J = 10.1, difluoroquinolin-4- 8.7,4.1 Hz, 1H), 7.49-7.41 (m, yl)benzimidazol-5- 2H), 6.77 (d, J = 2.2 Hz,1H), yl]morpholine 3.65 (dd, J = 6.0, 3.5 Hz, 4H), 3.11-2.90 (m, 4H),1.59 (td, J = 8.2, 4.1 Hz, 1H), 1.47-1.18 (m, 2H), 0.85 (dddd, J = 12.2,8.5, 6.3, 3.1 Hz, 2H). 182 4-[7-(5-chloro-4H-1,2,4- 510.2 1H NMR (400MHz, DMSO-d6) δ triazol-3-yl)-3-(5,8- 9.28 (d, J = 4.5 Hz, 1H), 8.00 (d,J = 4.5 Hz, difluoroquinolin-4-yl)- 1H), 7.77 (ddd, J = 9.9, 8.7,2-propylbenzimidazol- 4.2 Hz, 1H), 7.56-7.40 (m, 2H), 5-yl]morpholine6.77 (d, J = 2.2 Hz, 1H), 3.64 (dd, J = 5.9, 3.7 Hz, 4H), 3.13-2.92 (m,4H), 2.65 (td, J = 7.3, 2.8 Hz, 2H), 1.68 (h, J = 7.4 Hz, 2H), 0.80 (t,J = 7.4 Hz, 3H). 183 4-(1-(8-chloroquinolin- 445.2 1H NMR (400 MHz,DMSO-d6) δ 4-yl)-2-methyl-4-(1H- 9.32 (d, J = 4.5 Hz, 1H),pyrazol-4-yl)-1H- 8.48 (s, 2H), 8.12 (dd, J = 7.5, 1.2 Hz, 1H),benzo[d]imidazol-6- 7.98 (d, J = 4.5 Hz, 1H), 7.62 (dd, J = 8.,yl)morpholine 7.6 Hz, 1H), 7.41-7.28 (m, 2H), 6.33 (s, 1H), 3.66 (m,4H), 3.04 (m, 4H), 2.39 (s, 3H).

Step 6a:4-(1-(8-fluoroquinolin-4-yl)-2-methyl-4-(oxazol-2-yl)-1H-benzo[d]imidazol-6-yl)morpholine

To a solution of4-(4-bromo-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine(290 mg, 0.66 mmol) in dioxane (3.5 mL) were added2-(tri-n-butylstannyl)oxazole (0.21 mL, 0.99 mmol), copper iodide (13mg, 0.07 mmol), and Pd(II)Cl₂dppf (42 mg, 0.07 mmol). The resultingmixture was degassed under Argon and heated to 80° C. for 6 days. Thereaction was purified directly on silica (0-30% MeOH/DCM), then by prepLC to give4-(1-(8-fluoroquinolin-4-yl)-2-methyl-4-(oxazol-2-yl)-1H-benzo[d]imidazol-6-yl)morpholine(Compound 200). 1H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J=4.5 Hz, 1H), 8.45(d, J=0.8 Hz, 1H), 8.04 (d, J=4.5 Hz, 1H), 7.78 (ddd, J=10.8, 7.8, 1.2Hz, 1H), 7.69 (d, J=2.3 Hz, 1H), 7.68-7.62 (m, 1H), 7.61 (d, J=0.8 Hz,1H), 7.34 (d, J=8.4 Hz, 1H), 6.76 (d, J=2.2 Hz, 1H), 3.66 (t, J=4.8 Hz,4H), 3.08 (td, J=4.5, 2.8 Hz, 4H), 2.52 (s, 3H). ES/MS m/z 430.2 (M+H)⁺.

The compounds listed in the table below were prepared in a mannersimilar to that described above using appropriate intermediates andchemistry.

Compound Name MS NMR 201 4-[3-(8-chloroquinolin- 459.15 1H NMR (400 MHz,DMSO-d6) δ 4-yl)-2-methyl-7-(2- 9.31 (d, J = 4.5 Hz, 1H), 8.40 (s,methyl-1H-imidazol-5- 1H), 8.11 (dd, J = 7.5, 1.2 Hz, 1H),yl)benzimidazol-5- 7.95 (d, J = 4.5 Hz, 1H), 7.61 (dd, J = 8.5,yl]morpholine 7.5 Hz, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.21 (dd, J = 8.4,1.2 Hz, 1H), 6.49 (d, J = 2.1 Hz, 1H), 3.68 (t, J = 4.8 Hz, 4H),3.10-2.95 (m, 4H), 2.72 (s, 3H), 2.35 (s, 3H). 2024-[3-(8-chloroquinolin- 459.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7-(3- 9.32 (d, J = 4.5 Hz, 1H), 9.29 (s,methylimidazol-4- 1H), 8.12 (dd, J = 7.5, 1.2 Hz, 1H),yl)benzimidazol-5- 7.99 (s, 1H), 7.96 (d, J = 4.5 Hz, yl]morpholine 1H),7.63 (dd, J = 8.5, 7.5 Hz, 1H), 7.25 (dd, J = 8.5, 1.2 Hz, 1H), 7.14 (d,J = 2.2 Hz, 1H), 6.64 (d, J = 2.2 Hz, 1H), 3.97 (s, 3H), 3.65 (t, J =4.8 Hz, 4H), 3.09-2.95 (m, 4H), 2.31 (s, 3H). 2034-[3-(8-chloroquinolin- 459.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7-(1- 9.31 (d, J = 4.5 Hz, 1H), 9.22 (s,methylimidazol-4- 1H), 8.55 (d, J = 1.5 Hz, 1H), yl)benzimidazol-5- 8.11(dd, J = 7.6, 1.2 Hz, 1H), 7.96 (d, J = 4.5 Hz, yl]morpholine 1H),7.65-7.56 (m, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.21 (dd, J = 8.4, 1.2 Hz,1H), 6.51 (d, J = 2.1 Hz, 1H), 4.01 (s, 3H), 3.67 (t, J = 4.7 Hz, 4H),3.10-2.96 (m, 4H), 2.37 (s, 3H). 204 4-[3-(8-chloroquinolin- 446.1 1HNMR (400 MHz, DMSO-d6) δ 4-yl)-2-methyl-7-(1,3- 9.34 (d, J = 4.5 Hz,1H), 8.43 (s, oxazol-2- 1H), 8.13 (dd, J = 7.5, 1.2 Hz, 1H),yl)benzimidazol-5- 8.03 (d, J = 4.5 Hz, 1H), 7.66 (d, J = 2.3 Hz,yl]morpholine 1H), 7.65-7.56 (m, 2H), 7.44 (d, J = 8.5 Hz, 1H), 6.74 (d,J = 2.3 Hz, 1H), 3.65 (t, J = 4.8 Hz, 4H), 3.13-3.00 (m, 4H), 2.48 (s,3H). 205 4-[3-(8-chloroquinolin- 476.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7-(4- 9.32 (d, J = 4.5 Hz, 1H), 8.11 (dd, J = 7.5,methyl-1,3-thiazol-2- 1.2 Hz, 1H), 7.99 (d, J = 4.5 Hz,yl)benzimidazol-5- 1H), 7.78 (d, J = 2.2 Hz, 1H), yl]morpholine 7.61(dd, J = 8.4, 7.6 Hz, 1H), 7.49-7.43 (m, 1H), 7.34 (dd, J = 8.5, 1.2 Hz,1H), 6.63 (d, J = 2.2 Hz, 1H), 3.67 (t, J = 4.7 Hz, 4H), 3.10-2.99 (m,4H), 2.51 (s, 3H), 2.40 (s, 3H). 206 4-[3-(5,8- 475.2 1H NMR (400 MHz,DMSO-d6) δ difluoroquinolin-4-yl)- 9.28 (d, J = 4.5 Hz, 1H), 8.40 (s,2-ethyl-7-(2-methyl-1H- 1H), 7.97 (d, J = 4.5 Hz, 1H), imidazol-5-7.84-7.72 (m, 1H), 7.51-7.39 (m, yl)benzimidazol-5- 2H), 6.61-6.55 (m,1H), 3.69 (t, J = 4.7 Hz, yl]morpholine 4H), 3.12-2.99 (m, 4H), 2.73 (s,3H), 2.70-2.54 (m, 2H), 1.22 (t, J = 7.5 Hz, 3H). 2074-[3-(8-chloroquinolin- 473.21 1H NMR (400 MHz, DMSO-d6) δ4-yl)-7-(1H-imidazol-5- 9.31 (d, J = 4.5 Hz, 1H), 9.30 (s, yl)-2- 1H),8.56 (s, 1H), 8.11 (dd, J = 7.5, propylbenzimidazol-5- 1.1 Hz, 1H), 7.97(d, J = 4.5 Hz, yl]morpholine 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.56 (d, J= 2.1 Hz, 1H), 7.18 (dd, J = 8.4, 1.2 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H),3.67 (t, J = 4.8 Hz, 4H), 3.10-2.96 (m, 4H), 2.59 (td, J = 7.4, 2.4 Hz,2H), 1.75-1.59 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H). 2084-[3-(8-fluoroquinolin- 429.2 1H NMR (400 MHz, DMSO-d6) δ4-yl)-7-(1H-imidazol-5- 9.28 (s, 1H), 9.25 (d, J = 4.5 Hz, yl)-2- 1H),8.54 (s, 1H), 7.96 (d, J = 4.5 Hz, methylbenzimidazol-5- 1H), 7.76 (dd,J = 10.8, 7.7 Hz, yl]morpholine 1H), 7.63 (td, J = 8.1, 4.9 Hz, 1H),7.55 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 2.0 Hz,1H), 3.68 (t, J = 4.8 Hz, 4H), 3.11-2.97 (m, 4H), 2.37 (s, 3H). 2094-[2-ethyl-3-(8- 443.2 1H NMR (400 MHz, DMSO-d6) δfluoroquinolin-4-yl)-7- 9.31 (s, 1H), 9.25 (d, J = 4.5 Hz,(1H-imidazol-5- 1H), 8.57 (s, 1H), 7.97 (d, J = 4.5 Hz,yl)benzimidazol-5- 1H), 7.75 (dd, J = 10.8, 7.7 Hz, yl]morpholine 1H),7.62 (td, J = 8.1, 4.9 Hz, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.05 (d, J =8.4 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H), 3.68 (t, J = 4.8 Hz, 4H),3.11-2.97 (m, 4H), 2.64 (ddt, J = 28.6, 16.0, 7.9 Hz, 2H), 1.22 (t, J =7.4 Hz, 3H). 210 4-[3-(8-fluoro-2- 443.2 1H NMR (400 MHz, DMSO-d6) δmethylquinolin-4-yl)-7- 9.28 (d, J = 1.4 Hz, 1H), 8.54 (d, J = 1.3 Hz,(1H-imidazol-5-yl)-2- 1H), 7.85 (s, 1H), methylbenzimidazol-5- 7.74-7.64(m, 1H), 7.56 (d, J = 2.2 Hz, yl]morpholine 1H), 7.52 (dt, J = 7.9, 4.0Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 2.1 Hz, 1H), 3.68 (t, J= 4.8 Hz, 4H), 3.12-2.97 (m, 4H), 2.82 (s, 3H), 2.38 (s, 3H). 2114-[2-ethyl-3-(8-fluoro-2- 457.27 1H NMR (400 MHz, DMSO-d6) δmethylquinolin-4-yl)-7- 9.30 (s, 1H), 8.57 (s, 1H), 7.86 (s,(1H-imidazol-5- 1H), 7.68 (m, 1H), 7.57 (d, J = 2.1 Hz,yl)benzimidazol-5- 1H), 7.52 (m, 1H), 6.95 (d, J = 8.4 Hz, yl]morpholine1H), 6.50 (d, J = 2.1 Hz, 1H), 3.68 (t, J = 4.8 Hz, 4H), 3.12-2.93 (m,4H), 2.82 (s, 3H), 2.64 (m, 2H), 1.22 (t, J = 7.4 Hz, 3H). 2124-[3-(8-chloroquinolin- 487.2 1H NMR (400 MHz, DMSO-d6) δ4-yl)-7-(2-methyl-1H- 9.31 (d, J = 4.5 Hz, 1H), 8.41 (s,imidazol-5-yl)-2- 1H), 8.11 (d, J = 7.6 Hz, 1H), propylbenzimidazol-5-7.95 (d, J = 4.6 Hz, 1H), 7.60 (app. t, yl]morpholine 1H), 7.44 (d, J =2.1 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 3.67(t, J = 4.8 Hz, 4H), 3.08-2.95 (m, 4H), 2.72 (s, 3H), 2.58 (t, J = 7.5Hz, 2H), 1.71-1.59 (m, 2H), 0.82 (t, J = 7.3 Hz, 3H). 2134-[2-ethyl-3-(8- 444.2 1H NMR (400 MHz, DMSO-d6) δfluoroquinolin-4-yl)-7- 9.28 (d, J = 4.5 Hz, 1H), 8.43 (d, J = 0.8 Hz,(1,3-oxazol-2- 1H), 8.05 (d, J = 4.5 Hz, yl)benzimidazol-5- 1H), 7.77(ddd, J = 10.8, 7.8, 1.2 Hz, yl]morpholine 1H), 7.66 (d, J = 2.3 Hz,1H), 7.65-7.59 (m, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.23 (d, J = 8.4 Hz,1H), 6.70 (d, J = 2.3 Hz, 1H), 3.65 (t, J = 4.8 Hz, 4H), 3.05 (td, J =4.3, 2.3 Hz, 4H), 2.78 (q, J = 7.5 Hz, 2H), 1.10 (t, J = 7.5 Hz, 3H).214 4-[2-cyclopropyl-3-(8- 456.2 1H NMR (400 MHz, DMSO-d6) δfluoroquinolin-4-yl)-7- 9.26 (d, J = 4.5 Hz, 1H), 8.36 (d, J = 0.8 Hz,(1,3-oxazol-2- 1H), 8.00 (d, J = 4.5 Hz, yl)benzimidazol-5- 1H), 7.75(ddd, J = 10.8, 7.8, 1.2 Hz, yl]morpholine 1H), 7.64 (td, J = 8.1, 5.1Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 0.8 Hz, 1H), 7.24-7.17(m, 1H), 6.66 (d, J = 2.3 Hz, 1H), 3.66 (t, J = 4.7 Hz, 4H), 3.03 (td, J= 4.3, 1.9 Hz, 4H), 1.70-1.58 (m, 1H), 1.26-1.08 (m, 2H), 0.95 (tdd, J =8.9, 6.2, 3.2 Hz, 1H), 0.89-0.78 (m, 1H). 215 4-[3-(8-chloroquinolin-476.19 1H NMR (400 MHz, DMSO-d6) δ 4-yl)-2-methyl-7-(5- 9.32 (d, J = 4.5Hz, 1H), 8.12 (dd, J = 7.5, methyl-1,3-thiazol-2- 1.2 Hz, 1H), 8.00 (d,J = 4.5 Hz, yl)benzimidazol-5- 1H), 7.76-7.70 (m, 2H), yl]morpholine7.61 (dd, J = 8.5, 7.5 Hz, 1H), 7.36 (dd, J = 8.5, 1.2 Hz, 1H), 6.62 (d,J = 2.2 Hz, 1H), 3.66 (t, J = 4.7 Hz, 4H), 3.10-2.98 (m, 4H), 2.58 (d, J= 1.2 Hz, 3H), 2.42 (s, 3H). 216 4-[3-(8-chloroquinolin 490.2 1H NMR(400 MHz, DMSO-d6) δ 4-yl)-7-(4,5-dimethyl- 9.31 (d, J = 4.5 Hz, 1H),8.11 (dd, J = 7.5, 1,3-thiazol-2-yl)-2- 1.2 Hz, 1H), 7.98 (d, J = 4.5Hz, methylbenzimidazol-5- 1H), 7.72 (d, J = 2.3 Hz, 1H), yl]morpholine7.61 (dd, J = 8.5, 7.5 Hz, 1H), 7.33 (dd, J = 8.5, 1.2 Hz, 1H), 6.59 (d,J = 2.2 Hz, 1H), 3.66 (t, J = 4.7 Hz, 4H), 3.09-2.97 (m, 4H), 2.46 (d, J= 0.9 Hz, 3H), 2.40 (d, J = 0.9 Hz, 3H), 2.39 (s, 3H). 217 4-[3-(5,8-462.2 1H NMR (400 MHz, DMSO-d6) δ difluoroquinolin-4-yl)- 9.33 (d, J =4.5 Hz, 1H), 8.42 (d, J = 0.8 Hz, 2-ethyl-7-(1,3-oxazol-2- 1H), 8.09 (d,J = 4.5 Hz, yl)benzimidazol-5- 1H), 7.81 (ddd, J = 10.1, 8.8, 4.2 Hz,yl]morpholine 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.56 (d, J = 0.8 Hz, 1H),7.54-7.45 (m, 1H), 6.83 (d, J = 2.2 Hz, 1H), 3.70-3.56 (m, 4H),3.12-3.05 (m, 4H), 2.79 (q, J = 7.6 Hz, 2H), 1.13 (t, J = 7.5 Hz, 3H).218 4-[3-(8-chloro-7- 478.2 1H NMR (400 MHz, DMSO-d6) δfluoroquinolin-4-yl)-2- 9.37 (d, J = 4.6 Hz, 1H), 8.43 (d, J = 0.8 Hz,ethyl-7-(1,3-oxazol-2- 1H), 8.05 (d, J = 4.6 Hz, yl)benzimidazol-5- 1H),7.76 (t, J = 9.1 Hz, 1H), yl]morpholine 7.64 (d, J = 2.3 Hz, 1H), 7.56(d, J = 0.9 Hz, 1H), 7.49 (dd, J = 9.3, 5.6 Hz, 1H), 6.70 (d, J = 2.3Hz, 1H), 3.65 (t, J = 4.8 Hz, 4H), 3.11-2.99 (m, 4H), 2.77 (q, J = 7.6Hz, 2H), 1.10 (t, J = 7.5 Hz, 3H). 219 4-[3-(5,8- 490.2 1H NMR (400 MHz,DMSO-d6) δ difluoroquinolin-4-yl)- 9.33 (d, J = 4.5 Hz, 1H), 8.42 (d, J= 0.8 Hz, 2-(2-methylpropyl)-7- 1H), 8.09 (d, J = 4.5 Hz, (1,3-oxazol-2-1H), 7.81 (ddd, J = 10.0, 8.8, 4.2 Hz, yl)benzimidazol-5- 1H), 7.64 (d,J = 2.3 Hz, 1H), yl]morpholine 7.56 (d, J = 0.8 Hz, 1H), 7.55-7.45 (m,1H), 6.83 (d, J = 2.3 Hz, 1H), 3.67 (t, J = 4.8 Hz, 4H), 3.12-3.05 (m,4H), 2.77 (dd, J = 14.6, 6.8 Hz, 1H), 2.66 (dd, J = 14.5, 7.9 Hz, 1H),1.99-1.84 (m, 1H), 0.80 (dd, J = 6.6, 3.3 Hz, 6H). 2204-[3-(8-chloroquinolin- 486.2 1H NMR (400 MHz, DMSO-d6) δ 4-yl)-2- 9.35(d, J = 4.5 Hz, 1H), 8.44 (d, J = 0.8 Hz, (cyclopropylmethyl)-7- 1H),8.12 (dd, J = 7.5, 1.2 Hz, (1,3-oxazol-2- 1H), 8.08 (d, J = 4.5 Hz, 1H),yl)benzimidazol-5- 7.68 (d, J = 2.3 Hz, 1H), yl]morpholine 7.66-7.57 (m,2H), 7.38 (dd, J = 8.6, 1.2 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H), 3.65 (t,J = 4.8 Hz, 4H), 3.06 (td, J = 4.3, 1.9 Hz, 4H), 2.80 (d, J = 6.9 Hz,2H), 0.83-0.68 (m, 1H), 0.33-0.21 (m, 1H), 0.18-0.08 (m, 1H), 0.08-−0.03(m, 1H), −0.16-−0.27 (m, 1H). 221 4-[2- 488.2 1H NMR (400 MHz, DMSO-d6)δ (cyclopropylmethyl)-3- 9.34 (d, J = 4.5 Hz, 1H), 8.44 (d, J = 0.8 Hz,(5,8-difluoroquinolin-4- 1H), 8.12 (d, J = 4.5 Hz, yl)-7-(1,3-oxazol-2-1H), 7.81 (ddd, J = 10.0, 8.8, 4.2 Hz, yl)benzimidazol-5- 1H), 7.67 (d,J = 2.3 Hz, 1H), yl]morpholine 7.59 (d, J = 0.8 Hz, 1H), 7.49 (ddd, J =12.3, 8.8, 3.8 Hz, 1H), 6.86 (d, J = 2.3 Hz, 1H), 3.71-3.63 (m, 4H),3.16-3.06 (m, 4H), 2.84 (qd, J = 15.2, 7.0 Hz, 2H), 0.88-0.73 (m, 1H),0.36-0.24 (m, 1H), 0.19 (dddd, J = 9.2, 7.9, 5.7, 4.1 Hz, 1H), 0.06 (dq,J = 9.6, 5.0 Hz, 1H), −0.12-−0.23 (m, 1H). 222 4-[3-(8-chloro-6- 492.21H NMR (400 MHz, DMSO-d6) δ fluoroquinolin-4-yl)-7- 9.31 (d, J = 4.5 Hz,1H), 8.44 (d, J = 0.8 Hz, (1,3-oxazol-2-yl)-2- 1H), 8.24 (dd, J = 8.5,2.7 Hz, propylbenzimidazol-5- 1H), 8.10 (d, J = 4.5 Hz, 1H),yl]morpholine 7.67 (d, J = 2.3 Hz, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.29(d, J = 8.9 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H), 3.66 (t, J = 4.8 Hz, 4H),3.13-3.00 (m, 4H), 2.87-2.66 (m, 2H), 1.67-1.43 (m, 2H), 0.79 (t, J =7.4 Hz, 3H). 223 4-[3-(8-fluoroquinolin 458.2 1H NMR (400 MHz, DMSO-d6)δ 4-yl)-7-(1,3-oxazol-2- 9.28 (d, J = 4.5 Hz, 1H), 8.43 (d, J = 0.8 Hz,yl)-2- 1H), 8.05 (d, J = 4.5 Hz, propylbenzimidazol-5- 1H), 7.77 (ddd, J= 10.8, 7.8, 1.2 Hz, yl]morpholine 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.63(dd, J = 7.8, 5.0 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.22 (d, J = 8.5Hz, 1H), 6.69 (d, J = 2.3 Hz, 1H), 3.65 (t, J = 4.7 Hz, 4H), 3.05 (td, J= 4.3, 2.2 Hz, 4H), 2.86-2.66 (m, 2H), 1.63-1.43 (m, 2H), 0.77 (t, J =7.4 Hz, 3H). 224 4-[3-(8-chloroquinolin- 432.2 1H NMR (400 MHz, DMSO-d6)δ 4-yl)-7-(1,3-oxazol-2- 9.28 (d, J = 4.6 Hz, 1H), 8.89 (s,yl)benzimidazol-5- 1H), 8.40 (d, J = 0.8 Hz, 1H), yl]morpholine 8.13(dd, J = 7.5, 1.3 Hz, 1H), 8.00 (d, J = 4.5 Hz, 1H), 7.71 (d, J = 2.3Hz, 1H), 7.65 (dd, J = 8.5, 7.5 Hz, 1H), 7.55 (dd, J = 8.5, 1.3 Hz, 1H),7.53 (d, J = 0.8 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 3.69 (t, J = 4.8 Hz,4H), 3.10 (br s, 4H). 225 4-[2- 470.2 1H NMR (400 MHz, DMSO-d6) δ(cyclopropylmethyl)-3- 9.28 (d, J = 4.5 Hz, 1H), 8.44 (d, J = 0.9 Hz,(8-fluoroquinolin-4-yl)- 1H), 8.06 (d, J = 4.5 Hz, 7-(1,3-oxazol-2- 1H),7.77 (ddd, J = 10.8, 7.8, 1.2 Hz, yl)benzimidazol-5- 1H), 7.68 (d, J =2.3 Hz, 1H), yl]morpholine 7.63 (td, J = 8.2, 5.0 Hz, 1H), 7.58 (d, J =0.8 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 3.66(t, J = 4.7 Hz, 4H), 3.06 (td, J = 4.4, 2.4 Hz, 4H), 2.79 (d, J = 6.9Hz, 2H), 0.84-0.69 (m, 1H), 0.33-0.21 (m, 1H), 0.13 (dddd, J = 9.0, 7.9,5.7, 4.2 Hz, 1H), 0.02 (ddt, J = 9.2, 5.6, 4.6 Hz, 1H), −0.21 (ddt, J =9.1, 5.5, 4.4 Hz, 1H). 226 4-[3-(8-chloroquinolin 460.2 1H NMR (400 MHz,DMSO-d6) δ 4-yl)-2-ethyl-7-(1,3- 9.34 (d, J = 4.5 Hz, 1H), 8.43 (s,oxazol-2- 1H), 8.12 (d, J = 7.5 Hz, 1H), yl)benzimidazol-5- 8.06 (d, J =4.5 Hz, 1H), 7.68-7.64 (m, yl]morpholine 1H), 7.64-7.58 (m, 1H), 7.57(s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 2.2 Hz, 1H), 3.65 (t, J= 4.7 Hz, 4H), 3.12-2.98 (m, 4H), 2.76 (q, J = 7.5 Hz, 2H), 1.10 (td, J= 7.5, 0.7 Hz, 3H). 227 4-[3-(8-chloroquinolin- 474.2 1H NMR (400 MHz,DMSO-d6) δ 4-yl)-7-(1,3-oxazol-2- 9.34 (d, J = 4.5 Hz, 1H), 8.42 (s,yl)-2- 1H), 8.12 (d, J = 7.5 Hz, 1H), propylbenzimidazol-5- 8.05 (d, J =4.5 Hz, 1H), 7.64 (d, J = 2.2 Hz, yl]morpholine 1H), 7.61 (dd, J = 7.9,7.4 Hz, 1H), 7.56 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 2.2Hz, 1H), 3.65 (t, J = 4.8 Hz, 4H), 3.10-2.98 (m, 4H), 2.82-2.63 (m, 2H),1.63-1.43 (m, 2H), 0.77 (t, J = 7.3 Hz, 3H). 228 4-[3-(8-chloroquinolin-472.2 1H NMR (400 MHz, DMSO-d6) δ 4-yl)-2-cyclopropyl-7- 9.32 (d, J =4.5 Hz, 1H), 8.36 (s, (1,3-oxazol-2- 1H), 8.11 (d, J = 7.5 Hz, 1H),yl)benzimidazol-5- 8.01 (d, J = 4.5 Hz, 1H), 7.62 (dd, J = 8.4,yl]morpholine 7.5 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.47 (s, 1H), 7.34(d, J = 8.5 Hz, 1H), 6.66 (d, J = 2.0 Hz, 1H), 3.65 (t, J = 4.7 Hz, 4H),3.09-2.95 (m, 3H), 1.68-1.56 (m, 1H), 1.26-1.07 (m, 2H), 1.00-0.88 (m,1H), 0.88-0.76 (m, 1H). 229 4-[3-(5,8- 448.2 1H NMR (400 MHz, DMSO-d6) δdifluoroquinolin-4-yl)- 9.35 (d, J = 4.5 Hz, 1H), 8.44 (d, J = 0.8 Hz,2-methyl-7-(1,3-oxazol- 1H), 8.09 (d, J = 4.5 Hz, 2-yl)benzimidazol-5-1H), 7.82 (ddd, J = 10.1, 8.8, 4.3 Hz, yl]morpholine 1H), 7.67 (d, J =2.3 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.52 (ddd, J = 12.4, 8.8, 3.8 Hz,1H), 6.91 (d, J = 2.3 Hz, 1H), 3.75-3.58 (m, 4H), 3.15-3.07 (m, 4H),2.55 (s, 3H). 230 4-[3-(5,8- 476.2 1H NMR (400 MHz, DMSO-d6) δdifluoroquinolin-4-yl)- 9.34 (d, J = 4.5 Hz, 1H), 8.43 (d, J = 0.8 Hz,7-(1,3-oxazol-2-yl)-2- 1H), 8.10 (d, J = 4.5 Hz, propylbenzimidazol-5-1H), 7.81 (ddd, J = 10.0, 8.8, 4.2 Hz, yl]morpholine 1H), 7.65 (d, J =2.2 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.51 (ddd, J = 12.4, 8.8, 3.8 Hz,1H), 6.84 (d, J = 2.3 Hz, 1H), 3.73-3.58 (m, 4H), 3.13-3.05 (m, 4H),2.89-2.71 (m, 2H), 1.56 (qd, J = 7.4, 1.2 Hz, 2H), 0.81 (t, J = 7.4 Hz,3H). 231 4-[2-cyclopropyl-3-(5,8- 474.2 1H NMR (400 MHz, DMSO-d6) δdifluoroquinolin-4-yl)- 9.31 (d, J = 4.5 Hz, 1H), 8.35 (d, J = 0.8 Hz,7-(1,3-oxazol-2- 1H), 8.04 (d, J = 4.5 Hz, yl)benzimidazol-5- 1H), 7.78(ddd, J = 10.1, 8.7, 4.2 Hz, yl]morpholine 1H), 7.54 (d, J = 2.3 Hz,1H), 7.52-7.45 (m, 1H), 7.47 (d, J = 0.8 Hz, 1H), 6.79 (d, J = 2.3 Hz,1H), 3.73-3.58 (m, 4H), 3.10-3.02 (m, 4H), 1.75-1.63 (m, 1H), 1.25-1.14(m, 1H), 1.17-1.04 (m, 1H), 0.98-0.81 (m, 2H). 232 4-[2-ethyl-3-(8-474.2 1H NMR (400 MHz, DMSO-d6) δ fluoroquinolin-4-yl)-7- 9.25 (d, J =4.5 Hz, 1H), 8.00 (d, J = 4.5 Hz, (4-methyl-1,3-thiazol-2- 1H), 7.82 (d,J = 2.3 Hz, yl)benzimidazol-5- 1H), 7.75 (ddd, J = 10.8, 7.8, 1.2 Hz,yl]morpholine 1H), 7.62 (ddd, J = 8.5, 7.7, 5.0 Hz, 1H), 7.47 (q, J =0.8 Hz, 1H), 7.15 (dt, J = 8.4, 0.9 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H),3.68 (t, J = 4.7 Hz, 4H), 3.12-2.99 (m, 4H), 2.79-2.55 (m, 2H), 2.51 (s,3H), 1.22 (t, J = 7.5 Hz, 3H). 233 4-[3-(5,8- 478.1 1H NMR (400 MHz,DMSO-d6) δ difluoroquinolin-4-yl)- 9.30 (d, J = 4.5 Hz, 1H), 8.01 (d, J= 4.5 Hz, 2-methyl-7-(4-methyl- 1H), 7.79 (ddd, J = 10.1, 1,3-thiazol-2-8.8, 4.4 Hz, 1H), 7.76 (d, J = 2.2 Hz, yl)benzimidazol-5- 1H), 7.53-7.42(m, 2H), yl]morpholine 6.77 (d, J = 2.2 Hz, 1H), 3.72-3.65 (m, 4H),3.12-3.05 (m, 4H), 2.51 (s, 3H), 2.41 (s, 3H). 2344-[3-(8-chloroquinolin- 502.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-cyclopropyl-7- 9.32 (d, J = 4.5 Hz, 1H), 8.11 (dd, J = 7.5,(4-methyl-1,3-thiazol-2- 1.2 Hz, 1H), 8.02 (d, J = 4.5 Hz,yl)benzimidazol-5- 1H), 7.80 (d, J = 2.3 Hz, 1H), yl]morpholine 7.63(dd, J = 8.5, 7.5 Hz, 1H), 7.43 (q, J = 0.8 Hz, 1H), 7.36 (dd, J = 8.5,1.3 Hz, 1H), 6.66 (d, J = 2.3 Hz, 1H), 3.68 (t, J = 4.8 Hz, 4H), 3.05(dd, J = 6.4, 3.6 Hz, 4H), 2.48 (d, J = 1.0 Hz, 3H), 1.68-1.57 (m, 1H),1.28-1.12 (m, 1H), 1.04-0.93 (m, 1H), 0.93-0.81 (m, 1H). 235 4-[3-(5,8-506.2 1H NMR (400 MHz, DMSO-d6) δ difluoroquinolin-4-yl)- 9.28 (d, J =4.5 Hz, 1H), 7.98 (d, J = 4.5 Hz, 7-(4-methyl-1,3-thiazol- 1H),7.83-7.72 (m, 1H), 2-yl)-2- 7.75 (d, J = 2.4 Hz, 1H), 7.46 (ddd,propylbenzimidazol-5- J = 12.4, 8.7, 3.8 Hz, 1H), 7.42 (m, yl]morpholine1H), 6.67 (d, J = 2.3 Hz, 1H), 3.71-3.64 (m, 4H), 3.08-3.00 (m, 4H),2.63-2.55 (m, 2H), 2.49-2.48 (m, 3H), 1.71 (h, J = 7.5 Hz, 2H), 0.89 (t,J = 7.4 Hz, 3H). 236 4-[3-(5,8- 434.1 1H NMR (400 MHz, DMSO-d6) δdifluoroquinolin-4-yl)- 9.25 (d, J = 4.6 Hz, 1H), 8.73 (s,7-(1,3-oxazol-2- 1H), 8.37 (d, J = 0.8 Hz, 1H), yl)benzimidazol-5- 7.99(d, J = 4.6 Hz, 1H), 7.79 (ddd, J = 10.0, yl]morpholine 8.7, 4.2 Hz,1H), 7.65 (d, J = 2.3 Hz, 1H), 7.50 (d, J = 0.8 Hz, 1H), 7.55-7.44 (m,1H), 6.98 (d, J = 2.3 Hz, 1H), 3.69 (t, J = 4.7 Hz, 4H), 3.16-3.04 (m,4H). 237 4-[2-cyclopropyl-3-(5,8- 504.2 1H NMR (400 MHz, DMSO-d6) δdifluoroquinolin-4-yl)- 9.36-9.29 (m, 1H), 8.20-8.10 (m,7-(4-methyl-1,3-thiazol- 1H), 7.84-7.72 (m, 1H), 7.60 (dd,2-yl)benzimidazol-5- J = 5.1, 1.1 Hz, 1H), 7.57-7.39 (m, yl]morpholine2H), 6.93-6.84 (m, 1H), 3.73-3.65 (m, 4H), 3.17-3.10 (m, 4H), 1.98-1.91(m, 3H), 1.66-1.56 (m, 1H), 1.54-1.21 (m, 1H), 1.04-0.69 (m, 1H),0.59-0.42 (m, 2H). 238 4-[3-(8-chloro-5- 494.1 1H NMR (400 MHz, DMSO-d6)δ fluoroquinolin-4-yl)-2- 9.36 (d, J = 4.5 Hz, 1H), 8.13 (dd, J = 8.6,methyl-7-(4-methyl-1,3- 5.0 Hz, 1H), 8.00 (d, J = 4.5 Hz, thiazol-2-1H), 7.75 (d, J = 2.3 Hz, 1H), yl)benzimidazol-5- 7.48 (dd, J = 11.9,8.5 Hz, 1H), yl]morpholine 7.43 (d, J = 1.0 Hz, 1H), 6.73 (d, J = 2.3Hz, 1H), 3.71-3.64 (m, 4H), 3.10-3.02 (m, 4H), 2.50 (s, 3H), 2.38 (s,3H). 239 4-[3-(5,8- 492.2 1H NMR (400 MHz, DMSO-d6) δdifluoroquinolin-4-yl)- 9.29 (d, J = 4.5 Hz, 1H),2-propyl-7-(1,3-thiazol- 8.05-7.99 (m, 2H), 7.90 (d, J = 3.3 Hz, 1H),2-yl)benzimidazol-5- 7.81 (d, J = 2.3 Hz, 1H), 7.78 (ddd, yl]morpholineJ = 10.1, 8.8, 4.2 Hz, 1H), 7.47 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 6.74(d, J = 2.2 Hz, 1H), 3.72-3.65 (m, 4H), 3.11-3.04 (m, 4H), 2.64 (dd, J =7.8, 6.9 Hz, 2H), 1.71 (h, J = 7.4 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H).240 4-[3-(8-chloro-5- 480.1 1H NMR (400 MHz, DMSO-d6) δfluoroquinolin-4-yl)-2- 9.37 (d, J = 4.5 Hz, 1H), 8.13 (dd, J = 8.5,methyl-7-(1,3-thiazol-2- 5.0 Hz, 1H), 8.03 (d, J = 3.3 Hz,yl)benzimidazol-5- 1H), 8.02 (d, J = 4.6 Hz, 1H), yl]morpholine 7.91 (d,J = 3.2 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.49 (dd, J = 11.9, 8.5 Hz,1H), 6.76 (d, J = 2.3 Hz, 1H), 3.71-3.64 (m, 4H), 3.07 (t, J = 4.9 Hz,4H), 2.41 (s, 3H). 241 4-[2-cyclopropyl-3-(5,8- 490.2 1H NMR (400 MHz,DMSO-d6) δ difluoroquinolin-4-yl)- 9.30 (d, J = 4.5 Hz, 1H), 8.04 (d, J= 4.5 Hz, 7-(1,3-thiazol-2- 1H), 7.98 (d, J = 3.3 Hz, yl)benzimidazol-5-1H), 7.87 (d, J = 3.3 Hz, 1H), yl]morpholine 7.81 (d, J = 2.2 Hz, 1H),7.78 (ddq, J = 10.0, 8.8, 4.1 Hz, 1H), 7.48 (ddd, J = 11.8, 8.8, 3.8 Hz,1H), 6.77 (d, J = 2.2 Hz, 1H), 3.73-3.65 (m, 4H), 3.11-3.04 (m, 4H),1.73-1.62 (m, 1H), 1.27-1.16 (m, 1H), 1.16-1.06 (m, 1H), 1.01-0.84 (m,2H). 242 4-[3-(8-chloro-5- 490.15 1H NMR (400 MHz, DMSO-d6) δfluoroquinolin-4-yl)-2- 9.39 (d, J = 4.6 Hz, 1H), 8.48 (s,cyclopropyl-7-(1,3- 1H), 8.17-8.09 (m, 2H), 7.64 (d, J = 2.2 Hz,oxazol-2- 1H), 7.53-7.29 (m, 2H), yl)benzimidazol-5- 6.96 (s, 1H), 3.69(t, J = 4.8 Hz, yl]morpholine 4H), 3.13 (t, J = 4.9 Hz, 4H), 1.75-1.43(m, 2H), 1.40-1.06 (m, 1H), 0.72-0.38 (m, 2H). 243 4-[3-(8-chloro-5-520.19 1H NMR (400 MHz, DMSO-d6) δ fluoroquinolin-4-yl)-2- 9.42-9.35 (m,1H), 8.21-8.02 (m, cyclopropyl-7-(4- 2H), 7.63-7.37 (m, 3H),methyl-1,3-thiazol-2- 6.94-6.85 (m, 1H), 3.68 (t, J = 4.5 Hz,yl)benzimidazol-5- 4H), 3.18-3.01 (m, 4H), yl]morpholine 1.98-1.91 (m,3H), 1.68-1.40 (m, 2H), 1.34-1.17 (m, 1H), 1.06-0.67 (m, 1H), 0.60-0.39(m, 1H). 244 4-[3-(8-chloroquinolin- 462.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7-(1,3- 9.30 (d, J = 4.5 Hz, 1H), 8.10 (dd, J = 7.5,thiazol-2- 1.2 Hz, 1H), 7.99 (dd, J = 3.2, yl)benzimidazol-5- 0.4 Hz,1H), 7.97 (d, J = 4.5 Hz, yl]morpholine 1H), 7.89 (dd, J = 3.3, 0.4 Hz,1H), 7.84 (d, J = 2.3 Hz, 1H), 7.61 (dd, J = 8.4, 7.5 Hz, 1H), 7.28 (dd,J = 8.4, 1.2 Hz, 1H), 6.57 (d, J = 2.3 Hz, 1H), 3.66 (t, J = 4.8 Hz,4H), 3.05-2.96 (m, 4H), 2.37 (s, 3H). 245 4-[3-(8-chloroquinolin- 473.21H NMR (400 MHz, DMSO-d6) δ 4-yl)-2-ethyl-7-(2- 9.31 (d, J = 4.5 Hz,1H), 8.43 (s, methyl-1H-imidazol-5- 1H), 8.11 (dd, J = 7.5, 1.3 Hz, 1H),yl)benzimidazol-5- 7.97 (d, J = 4.5 Hz, 1H), 7.61 (dd, J = 8.5,yl]morpholine 7.5 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.19 (dd, J = 8.4,1.3 Hz, 1H), 6.48 (d, J = 2.1 Hz, 1H), 3.67 (t, J = 4.8 Hz, 4H),3.10-2.96 (m, 4H), 2.74 (s, 3H), 2.70-2.52 (m, 2H), 1.20 (t, J = 7.5 Hz,3H). 246 4-[3-(8-chloroquinolin- 457.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7- 10.28 (d, J = 1.5 Hz, 1H), 9.31 (d, J = 4.5 Hz,pyrazin-2- 1H), 8.83-8.77 (m, 1H), ylbenzimidazol-5- 8.65 (d, J = 2.6Hz, 1H), 8.11 (dd, J = 7.6, yl]morpholine 1.2 Hz, 1H), 7.98 (d, J = 4.5Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.66-7.57 (m, 1H), 7.27 (dd, J = 8.5,1.2 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 3.66 (t, J = 4.7 Hz, 4H),3.08-2.96 (m, 4H), 2.37 (s, 3H). 247 4-(1-(8-chloro-5- 506.1 1H NMR (400MHz, DMSO-d6) δ fluoroquinolin-4-yl)-2- 9.36 (d, J = 4.5 Hz, 1H), 8.12(dd, J = 8.5, cyclopropyl-4-(thiazol- 4.9 Hz, 1H), 8.04 (d, J = 4.5 Hz,2-yl)-1H- 1H), 7.96 (d, J = 3.2 Hz, 1H), benzo[d]imidazol-6- 7.85 (d, J= 3.2 Hz, 1H), 7.77 (d, J = 2.3 Hz, yl)morpholine 1H), 7.49 (dd, J =11.8, 8.5 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H), 3.75-3.57 (m, 4H),3.07-3.00 (m, 4H), 1.71-1.60 (m, 1H), 1.26-1.03 (m, 2H), 0.99-0.82 (m,2H).

Step 6b:4-(4-(2-chloro-1H-imidazol-5-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine

To a solution of4-(4-bromo-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine(100 mg, 0.23 mmol) in dioxane (1 mL) was added2-chloro-1-THP-1H-imidazole-5-boronic acid pinacol ester (106 mg, 0.34mmol), cesium fluoride (100 mg, 0.66 mmol), copper iodide (4 mg, 0.023mmol), and Pd(II)Cl₂dppf (13 mg, 0.023 mmol). The resulting mixture wasdegassed under Argon and heated to 80° C. for 5 days. The reaction waspurified directly on silica (0-30% MeOH/DCM), then by prep LC to give4-(4-(2-chloro-1H-imidazol-5-yl)-1-(8-fluoroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholineas an off-white solid (Compound 260). 1H NMR (400 MHz, DMSO-d6) δ 9.25(d, J=4.5 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J=4.5 Hz, 1H), 7.82-7.70 (m,1H), 7.68-7.56 (m, 1H), 7.49 (s, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.35 (s,1H), 3.66 (t, J=4.8 Hz, 4H), 3.09-2.92 (m, 4H), 2.40 (s, 3H). ES/MS m/z463.2 (M+H)⁺.

The compounds listed in the table below were prepared in a mannersimilar to that described above using appropriate intermediates andchemistry.

Compound Name MS NMR 261 4-[3-(8-chloroquinolin- 444.15 1H NMR (400 MHz,DMSO-d6) δ 4-yl)-2-methyl-7-(1H- 11.52 (s, 1H), 9.28 (d, J = 4.5 Hz,pyrrol-2- 1H), 8.08 (dd, J = 7.5, 1.2 Hz, 1H), yl)benzimidazol-5- 7.95(d, J = 4.5 Hz, 1H), 7.58 (dd, J = 8.5, yl]morpholine 7.5 Hz, 1H),7.33-7.24 (m, 2H), 7.01 (ddt, J = 13.3, 2.6, 1.7 Hz, 2H), 6.27-6.14 (m,2H), 3.63 (t, J = 4.8 Hz, 4H), 2.99 (q, J = 4.7 Hz, 4H), 2.36 (s, 3H).262 4-[3-(8-chloroquinolin- 445.12 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7-(1H- 9.32 (d, J = 4.5 Hz, 1H), 8.10 (dd, J = 7.5,pyrazol-3- 1.2 Hz, 1H), 8.03 (d, J = 4.5 Hz, yl)benzimidazol-5- 1H),7.90 (d, J = 2.3 Hz, 1H), yl]morpholine 7.65-7.56 (m, 2H), 7.47 (dd, J =8.2, 1.2 Hz, 1H), 7.22 (d, J = 2.3 Hz, 1H), 6.47 (d, J = 2.1 Hz, 1H),3.63 (t, J = 4.8 Hz, 4H), 3.11-2.95 (m, 4H), 2.49 (s, 3H). 2634-[3-(8-chloroquinolin- 444.17 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7-(1H- 11.18 (d, J = 23.0 Hz, 1H), 9.34 (d, pyrrol-3- J =4.5 Hz, 1H), 8.13 (dd, J = 7.5, yl)benzimidazol-5- 1.3 Hz, 1H), 8.01 (d,J = 4.5 Hz, yl]morpholine 1H), 7.72 (br s, 1H), 7.63 (dd, J = 8.5, 7.5Hz, 1H), 7.49-7.37 (m, 1H), 7.26 (s, 1H), 6.95 (s, 1H), 6.78 (s, 1H),6.32 (s, 1H), 3.65 (t, J = 4.7 Hz, 4H), 3.11-2.96 (m, 4H), 2.44 (s, 3H).264 4-[3-(8-chloroquinolin- 522.2 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7-(1- 9.31 (d, J = 4.5 Hz, 1H), 8.34 (t, J = 2.0 Hz,methylsulfonylpyrrol-3- 1H), 8.11 (dd, J = 7.5, 1.2 Hz,yl)benzimidazol-5- 1H), 7.97 (d, J = 4.5 Hz, 1H), yl]morpholine 7.61(dd, J = 8.5, 7.5 Hz, 1H), 7.43-7.38 (m, 1H), 7.35 (d, J = 2.2 Hz, 1H),7.32-7.25 (m, 2H), 6.36 (s, 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.56 (s, 3H),3.04 (q, J = 5.0 Hz, 4H), 2.37 (s, 3H). 265 4-[2-methyl-3-quinolin-428.1 1H NMR (400 MHz, DMSO-d6) δ 4-yl-7-(1,3-thiazol-4- 9.33 (d, J =2.0 Hz, 1H), 9.23 (d, J = 4.5 Hz, yl)benzimidazol-5- 1H), 8.93 (d, J =2.0 Hz, yl]morpholine 1H), 8.28 (dd, J = 8.4, 1.0 Hz, 1H), 7.98-7.83 (m,3H), 7.71-7.62 (m, 1H), 7.41 (d, J = 8.4 Hz, 1H), 6.46 (s, 1H), 3.67 (t,J = 4.8 Hz, 4H), 3.04 (q, J = 4.6 Hz, 4H), 2.44 (s, 3H). 2664-[3-(8-chloroquinolin- 445.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-7-(1H-imidazol-5- 9.31 (d, J = 4.6 Hz, 1H), 9.27 (d, J = 1.4 Hz,yl)-2- 1H), 8.53 (d, J = 1.4 Hz, methylbenzimidazol-5- 1H), 8.11 (dd, J= 7.6, 1.2 Hz, 1H), yl]morpholine 7.96 (d, J = 4.6 Hz, 1H), 7.61 (dd, J= 8.5, 7.6 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.22 (dd, J = 8.5, 1.2 Hz,1H), 6.51 (d, J = 2.1 Hz, 1H), 3.67 (t, J = 4.8 Hz, 4H), 3.03 (q, J =4.3 Hz, 4H), 2.36 (s, 3H). 267 4-[3-(8-chloroquinolin- 495.03 1H NMR(400 MHz, DMSO-d6) δ 4-yl)-7-(5- 9.29 (d, J = 4.4 Hz, 1H), 8.10 (dd, J =7.6, chlorothiophen-2-yl)-2- 1.2 Hz, 1H), 7.98-7.90 (m,methylbenzimidazol-5- 2H), 7.65-7.56 (m, 1H), 7.32 (d, J = 2.1 Hz,yl]morpholine 1H), 7.26 (dd, J = 8.5, 1.2 Hz, 1H), 7.22 (dd, J = 4.0,0.5 Hz, 1H), 6.39 (d, J = 2.1 Hz, 1H), 3.65 (t, J = 4.7 Hz, 4H), 3.01(q, J = 4.4 Hz, 4H), 2.33 (s, 3H). 268 4-[3-(8-chloroquinolin- 459.1 1HNMR (400 MHz, DMSO-d6) δ 4-yl)-2-methyl-7-(5- 9.37 (d, J = 4.6 Hz, 1H),8.15 (dd, J = 7.5, methyl-1H-pyrazol-3- 1.2 Hz, 1H), 8.09 (d, J = 4.5Hz, yl)benzimidazol-5- 1H), 7.77 (d, J = 1.0 Hz, 1H), yl]morpholine 7.65(dd, J = 8.4, 7.5 Hz, 1H), 7.54 (dd, J = 8.6, 1.3 Hz, 1H), 7.30 (d, J =2.1 Hz, 1H), 6.58 (d, J = 2.2 Hz, 1H), 3.65 (t, J = 4.8 Hz, 4H),3.12-2.99 (m, 4H), 2.53 (s, 3H), 2.31 (s, 3H). 2694-[3-(8-chloroquinolin- 459.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7-(2- 9.32 (d, J = 4.5 Hz, 1H), 8.12 (dd, J = 7.5,methylpyrazol-3- 1.2 Hz, 1H), 7.99 (d, J = 4.5 Hz, yl)benzimidazol-5-1H), 7.68-7.60 (m, 1H), yl]morpholine 7.59 (d, J = 1.8 Hz, 1H),7.41-7.33 (m, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.57 (d, J = 2.2 Hz, 1H),6.56 (d, J = 1.8 Hz, 1H), 3.91 (s, 3H), 3.64 (t, J = 4.8 Hz, 4H), 3.02(q, J = 4.4 Hz, 4H), 2.35 (s, 3H). 270 4-[3-(8-chloroquinolin- 462.1 1HNMR (400 MHz, DMSO-d6) δ 4-yl)-2-methyl-7-(1,3- 9.37 (d, J = 1.9 Hz,1H), 9.35 (d, J = 4.5 Hz, thiazol-4- 1H), 8.88 (d, J = 2.0 Hz,yl)benzimidazol-5- 1H), 8.13 (dd, J = 7.5, 1.2 Hz, 1H), yl]morpholine8.04 (d, J = 4.5 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.63 (dd, J = 8.5,7.5 Hz, 1H), 7.44 (dd, J = 8.7, 1.3 Hz, 1H), 6.57 (d, J = 2.2 Hz, 1H),3.67 (t, J = 4.8 Hz, 4H), 3.08 (q, J = 4.2 Hz, 4H), 2.49 (s, 3H). 2714-[3-(8-chloroquinolin- 461.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7- 9.31 (d, J = 4.5 Hz, 1H), 8.11 (dd, J = 7.5,thiophen-2- 1.2 Hz, 1H), 8.08 (dd, J = 3.6, ylbenzimidazol-5- 1.2 Hz,1H), 7.97 (d, J = 4.5 Hz, yl]morpholine 1H), 7.67 (dd, J = 5.1, 1.1 Hz,1H), 7.61 (dd, J = 8.5, 7.5 Hz, 1H), 7.35-7.28 (m, 2H), 7.25 (dd, J =5.1, 3.6 Hz, 1H), 6.45 (d, J = 2.1 Hz, 1H), 3.66 (t, J = 4.7 Hz, 4H),3.11-2.97 (m, 4H), 2.36 (s, 3H). 272 4-[3-(8-chloroquinolin- 461.1 1HNMR (400 MHz, DMSO-d6) δ 4-yl)-2-methyl-7- 9.32 (d, J = 4.5 Hz, 1H),8.48 (d, J = 2.4 Hz, thiophen-3- 1H), 8.11 (dd, J = 7.5, 1.2 Hz,ylbenzimidazol-5- 1H), 8.02-7.94 (m, 2H), yl]morpholine 7.71 (dd, J =5.0, 3.0 Hz, 1H), 7.62 (dd, J = 8.5, 7.5 Hz, 1H), 7.37 (d, J = 2.2 Hz,1H), 7.32 (dd, J = 8.5, 1.2 Hz, 1H), 6.41 (d, J = 2.1 Hz, 1H), 3.66 (t,J = 4.8 Hz, 4H), 3.11-2.97 (m, 4H), 2.37 (s, 3H). 2735-[1-(8-chloroquinolin- 486.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-6- 9.30 (d, J = 4.5 Hz, 1H), 8.19 (d, J = 4.1 Hz,morpholin-4- 1H), 8.10 (dd, J = 7.5, 1.2 Hz, ylbenzimidazol-4- 1H), 8.04(d, J = 4.0 Hz, 1H), yl]thiophene-2- 7.96 (d, J = 4.5 Hz, 1H), 7.60 (dd,J = 8.5, carbonitrile 7.5 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.27 (dd, J= 8.5, 1.2 Hz, 1H), 6.51 (d, J = 2.1 Hz, 1H), 3.66 (t, J = 4.8 Hz, 4H),3.12-2.97 (m, 4H), 2.35 (s, 3H). 274 4-[3-(8-chloroquinolin- 445.1 1HNMR (400 MHz, DMSO-d6) δ 4-yl)-7-(furan-2-yl)-2- 9.31 (d, J = 4.5 Hz,1H), 8.11 (dd, J = 7.6, methylbenzimidazol-5- 1.2 Hz, 1H), 7.97 (d, J =4.5 Hz, yl]morpholine 1H), 7.89-7.83 (m, 1H), 7.66-7.55 (m, 2H), 7.36(d, J = 2.2 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.73 (dd, J = 3.4, 1.9Hz, 1H), 6.42 (d, J = 2.2 Hz, 1H), 3.65 (t, J = 4.7 Hz, 4H), 3.01 (q, J= 4.3 Hz, 4H), 2.38 (s, 3H). 275 4-[3-(8-chloroquinolin- 445.1 1H NMR(400 MHz, DMSO-d6) δ 4-yl)-7-(furan-3-yl)-2- 9.32 (d, J = 4.5 Hz, 1H),8.65 (dd, J = 1.6, methylbenzimidazol-5- 0.7 Hz, 1H), 8.11 (dd, J = 7.5,yl]morpholine 1.2 Hz, 1H), 7.97 (d, J = 4.5 Hz, 1H), 7.85 (t, J = 1.7Hz, 1H), 7.62 (dd, J = 8.4, 7.5 Hz, 1H), 7.37-7.28 (m, 3H), 6.41 (d, J =2.1 Hz, 1H), 3.67 (t, J = 4.8 Hz, 4H), 3.13-2.98 (m, 4H), 2.39 (s, 3H).276 4-[3-(8-chloroquinolin- 462.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7-(1,3- 9.30 (d, J = 4.4 Hz, 1H), 9.15 (d, J = 0.6 Hz,thiazol-5- 1H), 8.84 (t, J = 0.6 Hz, yl)benzimidazol-5- 1H), 8.10 (dd, J= 7.4, 1.2 Hz, 1H), yl]morpholine 7.95 (d, J = 4.5 Hz, 1H), 7.64-7.55(m, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 8.4, 1.2 Hz, 1H), 6.41(d, J = 2.2 Hz, 1H), 3.65 (t, J = 4.8 Hz, 4H), 3.07-2.94 (m, 4H), 2.33(s, 3H). 277 4-[3-(8-chloroquinolin- 446.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7-(1,3- 9.31 (d, J = 4.5 Hz, 1H), 8.57 (s, oxazol-5- 1H),8.11 (dd, J = 7.5, 1.2 Hz, 1H), yl)benzimidazol-5- 8.11 (s, 1H), 7.97(d, J = 4.5 Hz, yl]morpholine 1H), 7.61 (dd, J = 8.5, 7.5 Hz, 1H), 7.34(d, J = 2.2 Hz, 1H), 7.30 (dd, J = 8.5, 1.3 Hz, 1H), 6.52 (d, J = 2.2Hz, 1H), 3.66 (t, J = 4.7 Hz, 4H), 3.08-2.96 (m, 4H), 2.38 (s, 3H). 2784-[7-(2-chloro-1H- 479.11 1H NMR (400 MHz, DMSO-d6) δimidazol-5-yl)-3-(8- 13.61 (s, 1H), 9.32 (s, 1H),chloroquinolin-4-yl)-2- 8.34-8.14 (m, 1H), 8.12 (d, J = 7.4 Hz,methylbenzimidazol-5- 1H), 8.06-7.96 (m, 1H), yl]morpholine 7.70-7.56(m, 1H), 7.50 (s, 1H), 7.41-7.05 (m, 1H), 6.46-6.35 (m, 1H), 3.66 (t, J= 4.8 Hz, 4H), 3.11-2.95 (m, 4H), 2.46-2.05 (m, 3H). 2794-[7-(2-chloro-1H- 493.2 1H NMR (400 MHz, DMSO-d6) δimidazol-5-yl)-3-(8- 9.32 (d, J = 4.5 Hz, 1H), 8.21 (s,chloroquinolin-4-yl)-2- 1H), 8.11 (d, J = 7.5 Hz, 1H),ethylbenzimidazol-5- 8.01 (d, J = 4.5 Hz, 1H), 7.61 (dd, J = 8.5,yl]morpholine 7.5 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 8.4Hz, 1H), 6.39 (d, J = 2.1 Hz, 1H), 3.66 (t, J = 4.7 Hz, 4H), 3.09-2.97(m, 4H), 2.81-2.60 (m, 2H), 1.15 (t, J = 7.5 Hz, 3H). 2804-[7-(2-chloro-1H- 495.2 1H NMR (400 MHz, DMSO-d6) δimidazol-5-yl)-3-(5,8- 9.31 (d, J = 4.5 Hz, 1H), 8.19 (s,difluoroquinolin-4-yl)- 1H), 8.05 (d, J = 4.5 Hz, 1H),2-ethylbenzimidazol-5- 7.79 (ddd, J = 10.0, 8.8, 4.2 Hz, 1H),yl]morpholine 7.54-7.43 (m, 2H), 6.54 (d, J = 2.1 Hz, 1H), 3.78-3.54 (m,4H), 3.14-3.03 (m, 4H), 2.75 (qd, J = 7.7, 3.2 Hz, 2H), 1.17 (t, J = 7.5Hz, 3H). 281 4-[7-(2-chloro-1H- 507.2 1H NMR (400 MHz, DMSO-d6) δimidazol-5-yl)-3-(8- 9.33 (d, J = 4.5 Hz, 1H), 8.20 (s,chloroquinolin-4-yl)-2- 1H), 8.12 (dd, J = 7.6, 1.2 Hz, 1H),propylbenzimidazol-5- 8.02 (d, J = 4.5 Hz, 1H), 7.61 (dd, J = 8.5,yl]morpholine 7.5 Hz, 1H), 7.54 (d, J = 2.2 Hz, 2H), 7.32 (dd, J = 8.5,1.2 Hz, 1H), 6.41 (d, J = 2.2 Hz, 1H), 3.66 (t, J = 4.8 Hz, 4H),3.11-2.97 (m, 4H), 2.70 (t, J = 7.6 Hz, 2H), 1.69-1.47 (m, 2H), 0.81 (t,J = 7.3 Hz, 3H). 282 4-[7-(2-chloro-1H- 477.2 1H NMR (400 MHz, DMSO-d6)δ imidazol-5-yl)-3-(8- 8.18 (s, 1H), 7.91 (s, 1H), 7.71 (m, fluoro-2-1H), 7.60-7.50 (m, 2H), 7.20 (d, J = 8.4 Hz, methylquinolin-4-yl)-2-1H), 6.45 (d, J = 2.2 Hz, methylbenzimidazol-5- 1H), 3.67 (t, J = 4.8Hz, 4H), yl]morpholine 3.10-2.98 (m, 4H), 2.83 (s, 3H), 2.50 (s, 3H).283 4-[7-(2-chloro-1H- 491.2 1H NMR (400 MHz, DMSO-d6) δimidazol-5-yl)-2-ethyl- 8.21 (s, 1H), 7.91 (s, 1H), 3-(8-fluoro-2- 7.70(ddd, J = 10.9, 7.8, 1.1 Hz, 1H), methylquinolin-4- 7.58-7.48 (m, 2H),7.10 (d, J = 8.4 Hz, yl)benzimidazol-5- 1H), 6.45-6.39 (m, 1H),yl]morpholine 3.67 (t, J = 4.8 Hz, 4H), 3.12-2.98 (m, 4H), 2.82 (s, 3H),2.81-2.65 (m, 2H), 1.15 (t, J = 7.5 Hz, 3H). 284 4-[7-(2-chloro-1H-477.2 1H NMR (400 MHz, DMSO-d6) δ imidazol-5-yl)-2-ethyl- 9.25 (d, J =4.5 Hz, 1H), 8.21 (s, 3-(8-fluoroquinolin-4- 1H), 8.00 (d, J = 4.5 Hz,1H), yl)benzimidazol-5- 7.75 (ddd, J = 10.8, 7.8, 1.2 Hz, 1H),yl]morpholine 7.63 (ddd, J = 8.5, 7.8, 5.0 Hz, 1H), 7.53 (d, J = 2.3 Hz,1H), 7.17 (dd, J = 8.5, 1.0 Hz, 1H), 6.39 (d, J = 2.1 Hz, 1H), 3.67 (t,J = 4.7 Hz, 4H), 3.11-2.96 (m, 4H), 2.81-2.61 (m, 2H), 1.16 (t, J = 7.5Hz, 3H). 285 4-[7-(2-chloro-1H- 465.1 1H NMR (400 MHz, DMSO-d6) δimidazol-5-yl)-3-(8- 9.26 (d, J = 4.6 Hz, 1H), 8.66 (s,chloroquinolin-4- 1H), 8.20 (s, 1H), 8.12 (dd, J = 7.5,yl)benzimidazol-5- 1.3 Hz, 1H), 7.95 (d, J = 4.6 Hz, yl]morpholine 1H),7.64 (dd, J = 8.5, 7.4 Hz, 1H), 7.61-7.52 (m, 2H), 6.60 (d, J = 2.2 Hz,1H), 3.70 (t, J = 4.8 Hz, 4H), 3.12-2.97 (m, 4H). 286 4-[7-(2-chloro-1H-507.2 1H NMR (400 MHz, DMSO-d6) δ imidazol-5-yl)-2- 9.30 (d, J = 4.5 Hz,1H), 8.13 (s, cyclopropyl-3-(5,8- 1H), 8.02 (d, J = 4.5 Hz, 1H),difluoroquinolin-4- 7.78 (ddd, J = 10.0, 8.7, 4.1 Hz, 1H),yl)benzimidazol-5- 7.56 (d, J = 2.2 Hz, 1H), 7.47 (ddd, yl]morpholine J= 11.7, 8.8, 3.8 Hz, 1H), 6.68 (s, 1H), 3.79-3.68 (m, 4H), 3.19-3.12 (m,4H), 1.74-1.63 (m, 1H), 1.27-1.07 (m, 2H), 0.99-0.82 (m, 2H). 2874-[7-(2-chloro-1H- 489.2 1H NMR (400 MHz, DMSO-d6) δ imidazol-5-yl)-2-9.25 (d, J = 4.5 Hz, 1H), 8.14 (s, cyclopropyl-3-(8- 1H), 7.98 (d, J =4.5 Hz, 1H), fluoroquinolin-4- 7.75 (ddd, J = 10.8, 7.8, 1.2 Hz, 1H),yl)benzimidazol-5- 7.64 (ddd, J = 8.6, 7.8, 5.0 Hz, 1H), yl]morpholine7.55 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 6.52 (s, 1H),3.74-3.67 (m, 4H), 3.15-3.03 (m, 4H), 1.69-1.57 (m, 1H), 1.28-1.13 (m,2H), 1.02-0.80 (m, 2H). 288 4-[3-(8-chloro-5- 497.2 1H NMR (400 MHz,DMSO-d6) δ fluoroquinolin-4-yl)-7- 9.40 (d, J = 4.5 Hz, 1H), 8.16 (s,(2-chloro-1H-imidazol- 1H), 8.14 (dd, J = 8.6, 5.0 Hz, 1H), 5-yl)-2-8.06 (d, J = 4.5 Hz, 1H), methylbenzimidazol-5- 7.56-7.46 (m, 2H), 6.58(d, J = 2.2 Hz, 1H), yl]morpholine 3.77-3.54 (m, 4H), 3.12-3.04 (m, 4H),2.50 (s, 3H). 289 4-[3-(8-chloro-6- 497.18 1H NMR (400 MHz, DMSO-d6) δfluoroquinolin-4-yl)-7- 9.31 (d, J = 4.5 Hz, 1H), 8.24 (dd, J = 8.5,(2-chloro-1H-imidazol- 2.7 Hz, 1H), 8.17 (s, 1H), 5-yl)-2- 8.06 (d, J =4.6 Hz, 1H), 7.54 (d, J = 2.2 Hz, methylbenzimidazol-5- 1H), 7.36 (dd, J= 9.1, 2.7 Hz, yl]morpholine 1H), 6.48 (d, J = 2.2 Hz, 1H), 3.67 (t, J =4.7 Hz, 4H), 3.14-3.00 (m, 4H), 2.51 (s, 3H). 290 4-[7-(2-chloro-1H-505.2 1H NMR (400 MHz, DMSO-d6) δ imidazol-5-yl)-3-(8- 9.32 (d, J = 4.5Hz, 1H), 8.14 (s, chloroquinolin-4-yl)-2- 1H), 8.11 (dd, J = 7.5, 1.2Hz, 1H), cyclopropylbenzimidazol- 7.99 (d, J = 4.5 Hz, 1H), 7.62 (dd, J= 8.5, 5-yl]morpholine 7.5 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.34 (dd,J = 8.5, 1.3 Hz, 1H), 6.49 (s, 1H), 3.69 (t, J = 4.7 Hz, 4H), 3.11-3.04(m, 4H), 1.62 (tt, J = 8.2, 4.8 Hz, 1H), 1.28-1.10 (m, 2H), 1.01-0.89(m, 1H), 0.90-0.78 (m, 1H). 291 4-[7-(2-chloro-1H- 521.2 1H NMR (400MHz, DMSO-d6) δ imidazol-5-yl)-3-(8- 9.27 (d, J = 4.5 Hz, 1H), 8.32 (s,chloroquinolin-4-yl)-2- 1H), 8.09 (dd, J = 7.5, 1.2 Hz, 1H), (oxetan-3-7.84 (d, J = 4.5 Hz, 1H), yl)benzimidazol-5- 7.63-7.53 (m, 2H), 7.19(dd, J = 8.5, 1.3 Hz, yl]morpholine 1H), 6.39 (d, J = 2.1 Hz, 1H), 5.02(dd, J = 6.8, 5.5 Hz, 1H), 4.93 (dd, J = 6.8, 5.5 Hz, 1H), 4.68 (dd, J =8.6, 5.5 Hz, 1H), 4.51 (dd, J = 8.5, 5.5 Hz, 1H), 4.15 (tt, J = 8.5, 6.8Hz, 1H), 3.67 (t, J = 4.7 Hz, 4H), 3.11-2.92 (m, 4H). 2924-[7-(2-chloro-1H- 449.18 1H NMR (400 MHz, DMSO-d6) δimidazol-5-yl)-3-(8- 9.20 (d, J = 4.6 Hz, 1H), 8.72 (s,fluoroquinolin-4- 1H), 8.20 (s, 1H), 7.95 (d, J = 4.6 Hz,yl)benzimidazol-5- 1H), 7.76 (dd, J = 10.6, 7.7 Hz, yl]morpholine 1H),7.66 (td, J = 8.1, 5.0 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H), 7.42 (d, J =8.5 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 3.71 (t, J = 4.8 Hz, 4H), 3.09(t, J = 4.8 Hz, 4H). 293 4-[7-(2-chloro-1H- 463.2 1H NMR (400 MHz,DMSO-d6) δ imidazol-5-yl)-3-(7- 9.25 (d, J = 4.6 Hz, 1H), 8.17 (s,fluoroquinolin-4-yl)-2- 1H), 8.06 (ddd, J = 10.1, 2.4, 0.7 Hz,methylbenzimidazol-5- 1H), 7.90 (d, J = 4.6 Hz, 1H), yl]morpholine7.66-7.51 (m, 3H), 6.39 (d, J = 2.2 Hz, 1H), 3.66 (t, J = 4.7 Hz, 4H),3.12-2.98 (m, 4H), 2.49 (s, 3H). 294 4-[3-(8-chloro-7- 497.17 1H NMR(400 MHz, DMSO-d6) δ fluoroquinolin-4-yl)-7- 9.37 (d, J = 4.5 Hz, 1H),8.18 (s, (2-chloro-1H-imidazol- 1H), 8.01 (d, J = 4.6 Hz, 1H), 5-yl)-2-7.77 (t, J = 9.1 Hz, 1H), 7.58-7.49 (m, methylbenzimidazol-5- 2H), 6.44(d, J = 2.2 Hz, 1H), yl]morpholine 3.66 (t, J = 4.7 Hz, 4H), 3.11-2.98(m, 4H), 2.48 (s, 3H). 295 4-[3-(8-chloro-7- 511.2 1H NMR (400 MHz,DMSO-d6) δ fluoroquinolin-4-yl)-7- 9.36 (d, J = 4.5 Hz, 1H), 8.21 (s,(2-chloro-1H-imidazol- 1H), 8.01 (d, J = 4.6 Hz, 1H), 5-yl)-2- 7.75 (t,J = 9.1 Hz, 1H), 7.53 (d, J = 2.2 Hz, ethylbenzimidazol-5- 1H), 7.44(dd, J = 9.4, 5.7 Hz, yl]morpholine 1H), 6.42 (d, J = 2.2 Hz, 1H), 3.67(t, J = 4.7 Hz, 4H), 3.04 (td, J = 4.2, 2.1 Hz, 4H), 2.84-2.48 (m, 2H),1.15 (t, J = 7.5 Hz, 3H). 296 4-[3-(8-chloro-7- 523.2 1H NMR (400 MHz,DMSO-d6) δ fluoroquinolin-4-yl)-7- 9.35 (d, J = 4.6 Hz, 1H), 8.14 (s,(2-chloro-1H-imidazol- 1H), 7.99 (d, J = 4.6 Hz, 1H), 5-yl)-2- 7.75 (t,J = 9.1 Hz, 1H), 7.54 (d, J = 2.2 Hz, cyclopropylbenzimidazol- 1H), 7.44(dd, J = 9.4, 5.7 Hz, 5-yl]morpholine 1H), 6.53 (s, 1H), 3.70 (dd, J =5.5, 4.0 Hz, 4H), 3.09 (dd, J = 6.5, 3.6 Hz, 4H), 1.64 (tt, J = 8.3, 4.8Hz, 1H), 1.29-1.11 (m, 2H), 1.02-0.92 (m, 1H), 0.89-0.79 (m, 1H). 2974-[3-(8-chloroquinolin- 476.19 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7-(2- 9.30 (d, J = 4.5 Hz, 1H), 8.56 (s,methyl-1,3-thiazol-5- 1H), 8.10 (dd, J = 7.5, 1.2 Hz, 1H),yl)benzimidazol-5- 7.95 (d, J = 4.5 Hz, 1H), 7.60 (dd, J = 8.5,yl]morpholine 7.5 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.27 (dd, J = 8.5,1.2 Hz, 1H), 6.42 (d, J = 2.1 Hz, 1H), 3.65 (t, J = 4.7 Hz, 4H),3.09-2.95 (m, 4H), 2.74 (s, 3H), 2.33 (s, 3H). 298 4-[7-(2-chloro-1H-481.2 1H NMR (400 MHz, DMSO-d6) δ imidazol-5-yl)-3-(5,8- 9.33 (d, J =4.5 Hz, 1H), 8.16 (s, difluoroquinolin-4-yl)- 1H), 8.06 (d, J = 4.5 Hz,1H), 2-methylbenzimidazol- 7.81 (ddd, J = 10.1, 8.8, 4.3 Hz, 1H),5-yl]morpholin 7.56-7.45 (m, 2H), 6.58 (d, J = 2.2 Hz, 1H), 3.68 (t, J =4.8 Hz, 4H), 3.16-2.94 (m, 4H), 2.51 (s, 3H). 299 4-[7-(2-chloro-1H-509.2 1H NMR (400 MHz, DMSO-d6) δ imidazol-5-yl)-3-(5,8- 9.30 (d, J =4.5 Hz, 1H), 8.17 (s, difluoroquinolin-4-yl)- 1H), 8.02 (d, J = 4.5 Hz,1H), 2-propylbenzimidazol- 7.79 (ddd, J = 10.1, 8.8, 4.2 Hz, 1H),5-yl]morpholine 7.53-7.42 (m, 2H), 6.49 (s, 1H), 3.67 (t, J = 4.7 Hz,4H), 3.06 (dt, J = 5.6, 2.1 Hz, 4H), 2.74-2.61 (m, 2H), 1.71-1.56 (m,2H), 0.84 (t, J = 7.3 Hz, 3H). 300 4-[7-(2-chloro-1H- 523.2 1H NMR (400MHz, DMSO-d6) δ imidazol-5-yl)-3-(5,8- 9.30 (d, J = 4.5 Hz, 1H), 8.18(s, difluoroquinolin-4-yl)- 1H), 8.02 (d, J = 4.5 Hz, 1H), 2-(2- 7.79(ddd, J = 10.1, 8.8, 4.2 Hz, 1H), methylpropyl)benzimidazol- 7.54-7.43(m, 2H), 6.53 (s, 1H), 5-yl]morpholine 3.68 (t, J = 4.8 Hz, 4H),3.17-2.97 (m, 4H), 2.66 (dd, J = 14.9, 6.9 Hz, 1H), 2.57 (dd, J = 14.9,7.5 Hz, 1H), 2.02 (hept, J = 6.8 Hz, 1H), 0.84 (d, J = 6.6 Hz, 6H). 3014-[7-(2-chloro-1H- 519.2 1H NMR (400 MHz, DMSO-d6) δimidazol-5-yl)-3-(8- 9.33 (d, J = 4.5 Hz, 1H), 8.22 (s,chloroquinolin-4-yl)-2- 1H), 8.11 (dd, J = 7.5, 1.2 Hz, 1H),(cyclopropylmethyl)benzimidazol- 8.04 (d, J = 4.5 Hz, 1H), 7.61 (dd, J =8.5, 5- 7.5 Hz, 1H), 7.57 (d, J = 2.2 Hz, yl]morpholine 1H), 7.35 (dd, J= 8.5, 1.3 Hz, 1H), 6.45 (d, J = 2.2 Hz, 1H), 3.67 (t, J = 4.7 Hz, 4H),3.13-2.99 (m, 4H), 2.83-2.67 (m, 2H), 0.92-0.77 (m, 1H), 0.31 (dddd, J =9.1, 8.1, 5.7, 4.2 Hz, 1H), 0.18 (dddd, J = 9.1, 7.9, 5.7, 4.2 Hz, 1H),−0.11-−0.22 (m, 1H). 302 4-[7-(2-chloro-1H- 521.2 1H NMR (400 MHz,DMSO-d6) δ imidazol-5-yl)-2- 9.31 (d, J = 4.5 Hz, 1H), 8.19 (s,(cyclopropylmethyl)-3- 1H), 8.05 (d, J = 4.5 Hz, 1H),(5,8-difluoroquinolin-4- 7.79 (ddd, J = 10.0, 8.8, 4.2 Hz, 1H),yl)benzimidazol-5- 7.53 (s, 0H), 7.47 (ddd, J = 12.3, yl]morpholine 8.8,3.8 Hz, 1H), 6.58-6.52 (m, 1H), 3.68 (t, J = 4.7 Hz, 4H), 3.12-3.03 (m,4H), 2.76 (qd, J = 15.5, 6.8 Hz, 2H), 0.96-0.81 (m, 1H), 0.33 (dddd, J =9.7, 8.2, 5.6, 4.1 Hz, 1H), 0.23 (dddd, J = 9.2, 7.9, 5.6, 4.1 Hz, 1H),0.09-0.01 (m, 1H), −0.14 (dq, J = 9.6, 4.9 Hz, 1H). 3034-[3-(8-chloro-6- 525.2 1H NMR (400 MHz, DMSO-d6) δfluoroquinolin-4-yl)-7- 9.29 (d, J = 4.5 Hz, 1H), 8.23 (dd, J = 8.5,(2-chloro-1H-imidazol- 2.7 Hz, 1H), 8.19 (s, 1H), 5-yl)-2- 8.05 (d, J =4.5 Hz, 1H), 7.53 (d, J = 2.2 Hz, propylbenzimidazol-5- 1H), 7.16 (dd, J= 9.3, 2.6 Hz, yl]morpholine 1H), 6.42 (d, J = 2.2 Hz, 1H), 3.67 (t, J =4.7 Hz, 4H), 3.10-2.97 (m, 4H), 2.77-2.61 (m, 2H), 1.72-1.51 (m, 2H),0.83 (t, J = 7.4 Hz, 3H). 304 4-[7-(2-chloro-1H- 503.2 1H NMR (400 MHz,DMSO-d6) δ imidazol-5-yl)-2- 9.25 (d, J = 4.5 Hz, 1H), 8.23 (s,(cyclopropylmethyl)-3- 1H), 8.01 (d, J = 4.5 Hz, 1H),(8-fluoroquinolin-4- 7.75 (ddd, J = 10.8, 7.8, 1.2 Hz, 1H),yl)benzimidazol-5- 7.62 (td, J = 8.2, 5.0 Hz, 1H), yl]morpholine 7.55(d, J = 2.2 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 6.41 (s, 1H), 3.67 (t, J= 4.7 Hz, 4H), 3.13-2.97 (m, 4H), 2.79-2.64 (m, 2H), 0.93-0.78 (m, 1H),0.32 (dddd, J = 9.1, 8.1, 5.7, 4.1 Hz, 1H), 0.25-0.13 (m, 1H),0.10-−0.04 (m, 1H), −0.10-−0.21 (m, 1H) 305 4-[7-(2-chloro-1H- 491.2 1HNMR (400 MHz, DMSO-d6) δ imidazol-5-yl)-3-(8- 9.26 (d, J = 4.5 Hz, 1H),8.21 (s, fluoroquinolin-4-yl)-2- 1H), 8.01 (d, J = 4.5 Hz, 1H),propylbenzimidazol-5- 7.76 (ddd, J = 10.8, 7.8, 1.2 Hz, 1H),yl]morpholine 7.63 (td, J = 8.1, 5.0 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H),7.17 (d, J = 8.5 Hz, 1H), 6.42 (s, 1H), 3.67 (t, J = 4.7 Hz, 4H),3.12-2.98 (m, 4H), 2.70 (t, J = 7.5 Hz, 2H), 1.60 (qq, J = 13.8, 7.3 Hz,2H), 0.81 (t, J = 7.4 Hz, 3H). 306 4-[7-(2-chloro-1H- 445.2 1H NMR (400MHz, DMSO-d6) δ imidazol-5-yl)-2- 9.24 (d, J = 4.5 Hz, 1H), 8.29 (ddd,methyl-3-quinolin-4- J = 8.5, 1.3, 0.7 Hz, 1H), 8.18 (s,ylbenzimidazol-5- 1H), 7.99-7.90 (m, 1H), 7.92 (d, J = 4.5 Hz,yl]morpholine 1H), 7.67 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.55 (d, J =2.2 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 2.1 Hz, 1H), 3.66(t, J = 4.8 Hz, 4H), 3.11-2.97 (m, 4H), 2.48 (s, 3H). 3074-[3-(8-chloro-5- 523.1 1H NMR (400 MHz, DMSO-d6) δfluoroquinolin-4-yl)-7- 9.36 (d, J = 4.5 Hz, 1H), 8.12 (dd, J = 8.5,(2-chloro-1H-imidazol- 4.9 Hz, 1H), 8.11 (s, 1H), 5-yl)-2- 8.01 (d, J =4.5 Hz, 1H), cyclopropylbenzimidazol- 7.54-7.40 (m, 2H), 6.59 (s, 1H),3.70 (t, J = 4.8 Hz, 5-yl]morpholine 4H), 3.12-3.07 (m, 4H), 1.64 (td, J= 8.2, 4.2 Hz, 1H), 1.24-1.15 (m, 1H), 1.14-1.03 (m, 1H), 0.96-0.79 (m,2H). 308 4-[7-(2-chloro-1H- 467.1 1H NMR (400 MHz, DMSO-d6) δimidazol-5-yl)-3-(5,8- 9.65 (s, 1H), 9.21 (s, 1H), difluoroquinolin-4-8.74-8.00 (m, 1H), 8.00-7.68 (m, 2H), yl)benzimidazol-5- 7.63-7.26 (m,2H), 6.80-6.38 (m, yl]morpholine 1H), 4.11-3.72 (m, 4H), 3.24-2.95 (m,4H). 309 4-[3-(5-chloro-8- 497.1 1H NMR (400 MHz, DMSO-d6) δfluoroquinolin-4-yl)-7- 9.35 (d, J = 4.4 Hz, 1H), 8.17 (s,(2-chloro-1H-imidazol- 1H), 8.08 (d, J = 4.4 Hz, 1H), 5-yl)-2- 7.84 (s,1H), 7.82 (d, J = 1.5 Hz, 1H), methylbenzimidazol-5- 7.54 (d, J = 2.2Hz, 1H), 6.56 (d, J = 2.2 Hz, yl]morpholine 1H), 3.68 (t, J = 4.8 Hz,4H), 3.14-3.06 (m, 4H), 2.51 (s, 3H). 310 4-[3-(5-chloro-8- 511.1 1H NMR(400 MHz, DMSO-d6) δ fluoroquinolin-4-yl)-7- 9.33 (d, J = 4.4 Hz, 1H),8.21 (s, (2-chloro-1H-imidazol- 1H), 8.09 (d, J = 4.5 Hz, 1H), 5-yl)-2-7.85-7.76 (m, 2H), 7.55 (d, J = 2.2 Hz, ethylbenzimidazol-5- 1H), 6.56(d, J = 2.2 Hz, 1H), yl]morpholine 3.69 (dd, J = 5.6, 4.0 Hz, 4H),3.17-3.06 (m, 4H), 2.85-2.68 (m, 2H), 1.20 (t, J = 7.5 Hz, 3H). 3114-(1-(8-chloroquinolin- 455.2 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-4- 9.36 (d, J = 4.5 Hz, 1H), 8.14 (dd, J = 7.5,phenyl-1H- 1.2 Hz, 1H), 8.04 (d, J = 4.5 Hz, benzo[d]imidazol-6- 1H),7.97-7.89 (m, 2H), yl)morpholine 7.70-7.55 (m, 3H), 7.56-7.43 (m, 2H),7.25 (d, J = 2.2 Hz, 1H), 6.58 (d, J = 2.2 Hz, 1H), 3.65 (t, J = 4.8 Hz,4H), 3.08 (q, J = 4.2 Hz, 4H), 2.43 (s, 3H). 312 4-(2-methyl-4-phenyl-1-497.3 1H NMR (400 MHz, DMSO-d6) δ (8-phenylquinolin-4-yl)- 9.24 (d, J =4.4 Hz, 1H), 1H-benzo[d]imidazol-6- 7.99-7.90 (m, 4H), 7.79-7.71 (m,3H), yl)morpholine 7.65-7.57 (m, 2H), 7.57-7.43 (m, 5H), 7.28 (d, J =2.2 Hz, 1H), 6.60 (d, J = 2.1 Hz, 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.10(q, J = 4.0 Hz, 4H), 2.46 (s, 3H). 313 4-(1-(8-chloroquinolin- 459.1 1HNMR (400 MHz, DMSO-d6) δ 4-yl)-2-methyl-4-(1- 9.33 (d, J = 4.6 Hz, 1H),8.56 (s, methyl-1H-pyrazol-4- 1H), 8.25 (d, J = 0.7 Hz, 1H), yl)-1H-8.13 (dd, J = 7.5, 1.2 Hz, 1H), 8.00 (d, J = 4.5 Hz, benzo[d]imidazol-6-1H), 7.63 (dd, J = 8.5, 7.6 Hz, yl)morpholine 1H), 7.43-7.30 (m, 2H),6.41 (d, J = 2.3 Hz, 1H), 3.97 (s, 3H), 3.67 (t, J = 4.7 Hz, 4H),3.14-2.99 (m, 4H), 2.42 (s, 3H). 314 4-(1-(8-chloroquinolin- 457.1 1HNMR (400 MHz, DMSO-d6) δ 4-yl)-2-methyl-4- 10.15 (dd, J = 2.5, 1.2 Hz,1H), (pyridazin-4-yl)-1H- 9.44-9.37 (m, 1H), 9.31 (d, J = 4.6 Hz,benzo[d]imidazol-6- 1H), 8.62 (dd, J = 5.5, 2.4 Hz, 1H), yl)morpholine8.11 (dd, J = 7.5, 1.2 Hz, 1H), 7.97 (d, J = 4.5 Hz, 1H), 7.61 (dd, J =8.5, 7.5 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 8.5, 1.2 Hz,1H), 6.61 (d, J = 2.2 Hz, 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.07 (q, J =4.5 Hz, 4H), 2.35 (s, 3H). 315 4-(1-(8-chloroquinolin- 457.1 1H NMR (400MHz, DMSO-d6) δ 4-yl)-2-methyl-4- 9.55 (s, 2H), 9.31 (d, J = 4.5 Hz,(pyrimidin-5-yl)-1H- 1H), 9.23 (s, 1H), 8.11 (dd, J = 7.5,benzo[d]imidazol-6- 1.2 Hz, 1H), 7.96 (d, J = 4.5 Hz, yl)morpholine 1H),7.61 (dd, J = 8.5, 7.5 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.27 (dd, J =8.5, 1.2 Hz, 1H), 6.52 (d, J = 2.2 Hz, 1H), 3.65 (t, J = 4.8 Hz, 4H),3.05 (q, J = 4.5 Hz, 4H), 2.34 (s, 3H). 316 3-(1-(8-chloroquinolin-498.2 1H NMR (400 MHz, DMSO-d6) δ 4-yl)-2-methyl-6- 9.35 (d, J = 4.7 Hz,1H), 8.14 (d, J = 7.5 Hz, morpholino-1H- 1H), 8.02 (d, J = 3.9 Hz,benzo[d]imidazol-4-yl)- 1H), 7.65 (t, J = 8.0 Hz, 1H),N,N-dimethylaniline 7.46 (br s, 1H), 7.45-7.36 (m, 1H), 7.29-7.12 (m,2H), 6.92 (br s, 1H), 6.53 (s, 2H), 3.65 (t, J = 4.8 Hz, 4H), 3.08-3.05(m, 4H), 3.03 (s, 6H), 2.42 (s, 3H). 317 4-[3-(8-chloroquinolin- 456.11H NMR (400 MHz, DMSO-d6) δ 4-yl)-2-methyl-7- 9.55 (s, 1H), 9.32 (d, J =4.5 Hz, pyridin-3- 1H), 8.98 (br d, J = 8.1 Hz, 1H), ylbenzimidazol-5-8.82 (dd, J = 5.3, 1.5 Hz, 1H), yl]morpholine 8.12 (dd, J = 7.5, 1.2 Hz,1H), 7.97 (d, J = 4.5 Hz, 1H), 7.96-7.90 (m, 1H), 7.62 (dd, J = 8.5, 7.5Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.27 (dd, J = 8.5, 1.3 Hz, 1H), 6.57(d, J = 2.2 Hz, 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.13-2.99 (m, 4H), 2.35(s, 3H). 318 4-[2-methyl-7-pyridin- 499.2 1H NMR (400 MHz, DMSO-d6) δ3-yl-3-(8-pyridin-3- 9.68-9.62 (m, 1H), 9.26 (d, J = 4.5 Hz,ylquinolin-4- 1H), 9.25-9.22 (m, 1H), yl)benzimidazol-5- 9.14 (dt, J =8.2, 1.8 Hz, 1H), 8.92 (td, J = 5.5, yl]morpholine 1.5 Hz, 2H), 8.73(dt, J = 8.1, 1.8 Hz, 1H), 8.15 (dd, J = 7.2, 1.4 Hz, 1H), 8.11-8.01 (m,2H), 7.98 (d, J = 4.5 Hz, 1H), 7.82 (dd, J = 8.5, 7.2 Hz, 1H), 7.48 (d,J = 2.2 Hz, 1H), 7.46 (dd, J = 8.5, 1.3 Hz, 1H), 6.61 (d, J = 2.1 Hz,1H), 3.69 (t, J = 4.8 Hz, 4H), 3.17-3.01 (m, 4H), 2.39 (s, 3H). 3194-[3-(8-chloroquinolin- 456.2 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7- 9.32 (d, J = 4.5 Hz, 1H), 8.95 (d, J = 6.6 Hz,pyridin-4- 2H), 8.85 (br d, J = 5.9 Hz, ylbenzimidazol-5- 2H), 8.11 (dd,J = 7.5, 1.2 Hz, 1H), yl]morpholine 7.97 (d, J = 4.6 Hz, 1H), 7.61 (dd,J = 8.5, 7.6 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.24 (dd, J = 8.5, 1.3Hz, 1H), 6.68 (d, J = 2.1 Hz, 1H), 3.67 (t, J = 4.8 Hz, 4H), 3.07 (q, J= 4.5 Hz, 4H), 2.35 (s, 3H). 320 4-[2-methyl-7-pyridin- 499.2 1H NMR(400 MHz, DMSO-d6) δ 4-yl-3-(8-pyridin-4- 9.27 (d, J = 4.5 Hz, 1H),ylquinolin-4- 9.09-8.97 (m, 6H), 8.42-8.34 (m, 2H), yl)benzimidazol-5-8.19 (dd, J = 7.2, 1.3 Hz, 1H), 8.01 (d, J = 4.5 Hz, yl]morpholine 1H),7.84 (dd, J = 8.5, 7.2 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.50 (dd, J =8.4, 1.3 Hz, 1H), 6.74 (d, J = 2.1 Hz, 1H), 3.70 (t, J = 4.8 Hz, 4H),3.18-3.02 (m, 4H), 2.40 (s, 3H). 321 3-[1-(8-chloroquinolin- 498.1 1HNMR (400 MHz, DMSO-d6) δ 4-yl)-2-methyl-6- 9.34 (d, J = 4.5 Hz, 1H),8.35 (t, J = 1.8 Hz, morpholin-4- 1H), 8.22-8.16 (m, 1H),ylbenzimidazol-4- 8.15-8.07 (m, 2H), 8.00 (d, J = 4.5 Hz, yl]benzamide1H), 7.95 (dt, J = 7.8, 1.4 Hz, 1H), 7.70-7.59 (m, 2H), 7.50 (s, 1H),7.39 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 2.2 Hz, 1H), 6.54 (d, J = 2.1 Hz,1H), 3.66 (t, J = 4.8 Hz, 4H), 3.14-2.99 (m, 4H), 2.39 (s, 3H). 3223-[4-[4-(3- 583.2 1H NMR (400 MHz, DMSO-d6) δ carbamoylphenyl)-2- 9.24(d, J = 4.5 Hz, 1H), 8.35 (t, J = 1.8 Hz, methyl-6-morpholin-4- 1H),8.22 (t, J = 1.8 Hz, ylbenzimidazol-1- 1H), 8.17 (d, J = 7.8 Hz, 1H),yl]quinolin-8- 8.12 (s, 1H), 8.07 (s, 1H), 8.03-7.93 (m, yl]benzamide4H), 7.90 (dt, J = 7.7, 1.3 Hz, 1H), 7.77 (dd, J = 8.4, 7.2 Hz, 1H),7.68 (t, J = 7.7 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.52 (s, 1H),7.50-7.45 (m, 1H), 7.43 (s, 1H), 7.31 (d, J = 2.2 Hz, 1H), 6.57 (d, J =2.1 Hz, 1H), 3.68 (t, J = 4.8 Hz, 4H), 3.17-3.03 (m, 4H), 2.44 (s, 3H).323 4-[3-(8-chloroquinolin- 456.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7- 9.37 (d, J = 4.5 Hz, 1H), pyridin-2- 8.92-8.86 (m,1H), 8.70 (d, J = 8.1 Hz, 1H), ylbenzimidazol-5- 8.20-8.11 (m, 2H), 8.07(d, J = 4.5 Hz, yl]morpholine 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.69-7.56(m, 2H), 7.49 (dd, J = 8.5, 1.2 Hz, 1H), 6.70 (d, J = 2.1 Hz, 1H), 3.68(t, J = 4.8 Hz, 4H), 3.19-3.04 (m, 4H), 2.54 (s, 3H).

Step 6c:4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazol-6-yl)morpholine

4-(4-Bromo-1-(8-chloroquinolin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine(220 mg, 0.48 mmol), ethynyltributylstannane (0.181 mL, 0.63 mmol),Pd(dppf)Cl2 (31 mg, 0.048 mmol), and copper iodide (9 mg, 0.048 mmol)were combined in dioxane (2 mL), degassed under Ar₂, and heated to 70°C. After 5 days the reaction was purified directly on silica to give4-(1-(8-chloroquinolin-4-yl)-4-ethynyl-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine.4-(1-(8-Chloroquinolin-4-yl)-4-ethynyl-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine(39 mg, 0.097 mmol) was combined with copper iodide (2 mg, 0.01 mmol) ina mixture of DMF (0.5 mL) and MeOH (0.1 mL) under N₂.Azidotrimethylsilane (0.019 mL, 0.145 mmol) was added, and the resultingmixture was heated to 80° C. overnight. Purification on silica (0-30%MeOH/DCM), followed by preparatory LC, provided4-(1-(8-chloroquinolin-4-yl)-2-methyl-4-(1H-1,2,3-triazol-5-yl)-1H-benzo[d]imidazol-6-yl)morpholine(Compound 329). 1H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J=4.5 Hz, 1H), 8.81(s, 1H), 8.11 (d, J=7.5 Hz, 1H), 7.99 (d, J=4.5 Hz, 1H), 7.68-7.48 (m,2H), 7.34 (s, 1H), 6.49 (s, 1H), 3.68-3.64 (m, 4H), 3.10-2.95 (m, 4H),2.41 (s, 3H). ES/MS m/z 446.2 (M+H)⁺.

The compounds listed in the table below were prepared in a mannersimilar to that described above using appropriate intermediates andchemistry.

Compound Name MS NMR 376 4-(1-(5,8- 462.2 1H NMR (400 MHz, DMSO-d6) δdifluoroquinolin-4-yl)- 9.31 (d, J = 28.5 Hz, 1H), 2-ethyl-4-(1H-1,2,3-8.89-8.72 (m, 1H), 8.11-7.91 (m, 1H), triazol-5-yl)-1H- 7.83-7.70 (m,1H), 7.69-7.55 (m, benzo[d]imidazol-6- 1H), 7.55-7.36 (m, 1H),yl)morpholine 6.67-6.50 (m, 1H), 3.68 (t, J = 4.7 Hz, 4H), 3.15-2.95 (m,4H), 1.26-1.09 (m, 3H), 0.72-0.55 (m, 2H). 377 4-(1-(5,8- 448.2 1H NMR(400 MHz, DMSO-d6) δ difluoroquinolin-4-yl)- 9.32 (d, J = 4.5 Hz, 1H),2-methyl-4-(1H-1,2,3- 8.86-8.76 (m, 1H), 8.04 (d, J = 4.5 Hz, 1H),triazol-5-yl)-1H- 7.80 (td, J = 9.4, 4.1 Hz, 1H), benzo[d]imidazol-6-7.64 (s, 1H), 7.50 (ddd, J = 12.3, 8.8, 3.8 Hz, yl)morpholine 1H), 6.65(s, 1H), 3.68 (t, J = 4.8 Hz, 4H), 3.09 (s, 4H), 2.48 (s, 3H). 3784-(1-(8-chloroquinolin- 472.2 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-cyclopropyl-4- 9.32 (d, J = 4.4 Hz, 1H),(1H-1,2,3-triazol-5-yl)- 8.80-8.67 (m, 1H), 8.10 (d, J = 7.5 Hz, 1H),1H-benzo[d]imidazol-6- 8.03-7.95 (m, 1H), 7.66-7.56 (m, yl)morpholine2H), 7.37-7.27 (m, 1H), 6.53-6.44 (m, 1H), 3.67 (t, J = 4.7 Hz, 4H),3.11-2.95 (m, 4H), 1.65-1.52 (m, 1H), 1.30-1.11 (m, 2H), 1.01-0.75 (m,2H).

Step 6d:4-(1-(5,8-difluoroquinolin-4-yl)-2-ethyl-4-(1H-imidazol-2-yl)-1H-benzo[d]imidazol-6-yl)morpholine

4-(4-bromo-1-(5,8-difluoroquinolin-4-yl)-2-ethyl-1H-benzo[d]imidazol-6-yl)morpholine(200 mg, 0.42 mmol) was combined with N,N-dimethylimidazole-1-sulfonamide (81 mg, 0.47 mmol), PdOAc (7 mg, 0.07 mmol), andCuI (210 mg, 1.1 mmol) in DMF (2 mL). The mixture was degassed under Ar₂and heated to 140° C. under microwave irradiation for 10 hours. Thereaction was filtered and the filtrate concentrated, then precipitatedfrom water to give the protected product as a brown solid. Treatmentwith TFA in DCM, followed by reverse phase prep LC purification,provided the title compound (Compound 387). 1H NMR (400 MHz, DMSO-d6) δ9.30 (d, J=4.5 Hz, 1H), 8.01 (d, J=4.5 Hz, 1H), 7.87 (s, 2H), 7.79 (ddd,J=10.0, 8.7, 4.2 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.52-7.41 (m, 1H),6.89 (d, J=2.1 Hz, 1H), 3.78-3.62 (m, 4H), 3.12-3.05 (m, 4H), 2.75-2.60(m, 2H), 1.25 (t, J=7.5 Hz, 3H). ES/MS m/z=461.2 (M+H)⁺.

Step 6e:4-(1-(5,8-difluoroquinolin-4-yl)-2-propyl-4-(1H-pyrazol-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine

To a solution of4-(4-bromo-1-(5,8-difluoroquinolin-4-yl)-2-propyl-1H-benzo[d]imidazol-6-yl)morpholine(100 mg, 0.21 mmol) in dioxane (1 mL) was added 1-Boc-pyrazole-4-boronicacid pinacol ester (91 mg, 0.31 mmol), cesium fluoride (78 mg, 0.51mmol), and BrettPhos Pd G3 (17 mg, 0.021 mmol). The resulting mixturewas degassed under Argon and heated to 80° C. for 3 days. The reactionwas purified directly on silica (0-100% EtOAc/DCM), then treated withTFA in DCM to remove the Boc group. Final purification by prep HPLCeluting with 5-95% water/acetonitrile (0.1% v/v trifluoroacetic acid)afforded the title compound (Compound 388). 1H NMR (400 MHz, DMSO-d6) δ9.30 (d, J=4.5 Hz, 1H), 8.50 (s, 2H), 8.00 (d, J=4.5 Hz, 1H), 7.79 (ddd,J=10.1, 8.8, 4.2 Hz, 1H), 7.48 (ddd, J=12.3, 8.8, 3.8 Hz, 1H), 7.35 (d,J=2.2 Hz, 1H), 6.47 (s, 1H), 3.74-3.52 (m, 4H), 3.15-3.03 (m, 4H),2.72-2.56 (m, 2H), 1.66 (h, J=7.4 Hz, 2H), 0.86 (t, J=7.4 Hz, 3H). ES/MSm/z 475.2 (M+H)⁺.

The compound listed in the table below was prepared in a manner similarto that described above using appropriate intermediates and chemistry.

Compound Name MS NMR 389 4-(1-(5,8- 475.20 1H NMR (400 MHz, DMSO-d6) δdifluoroquinolin-4-yl)- 9.34 (d, J = 4.5 Hz, 1H), 8.11 (d, J = 4.5 Hz,2-propyl-4-(1H-pyrazol- 1H), 7.89 (d, J = 2.2 Hz, 5-yl)-1H- 1H), 7.81(ddd, J = 10.1, 8.8, 4.2 Hz, benzo[d]imidazol-6- 1H), 7.59 (d, J = 2.2Hz, 1H), yl)morpholine 7.51 (ddd, J = 12.3, 8.8, 3.8 Hz, 1H), 7.29 (d, J= 2.2 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 3.68 (t, J = 4.7 Hz, 4H),3.15-3.02 (m, 4H), 2.87-2.74 (m, 2H), 1.59 (h, J = 7.6 Hz, 2H), 0.83 (t,J = 7.3 Hz, 3H).

Step 6f:4-(1-(5,8-difluoroquinolin-4-yl)-4-(2-(trifluoromethyl)-1H-imidazol-5-yl)-1H-benzo[d]imidazol-6-yl)morpholineas a yellow solid

4-(4-bromo-1-(5,8-difluoroquinolin-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine(150 mg, 0.337 mmol),2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(117 mg, 0.438 mmol), butyl di-1-adamantylphosphine tretrafluoroboratesalt (45 mg, 0.101 mmol), K₂CO₃ (116 mg, 0.842 mmol), Pd(OAc)₂ (11 mg,0.051 mmol), and pivalic acid (10 mg, 0.101 mmol) were combined intoluene (0.5 mL). The mixture was purged with N₂ and heated to 100° C.overnight. Purification on silica gel (12 g column, 0-100% EtOAc/DCM)gave4-(1-(5,8-difluoroquinolin-4-yl)-4-(2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-1H-benzo[d]imidazol-6-yl)morpholine,ES/MS m/z=631.2 (M+H)⁺. Treatment with TFA in DCM afforded the titlecompound (Compound 390). 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J=4.5 Hz,1H), 8.55 (s, 1H), 8.34 (s, 1H), 7.90 (d, J=4.6 Hz, 1H), 7.72 (ddd,J=10.1, 8.8, 4.2 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.42 (ddd, J=12.5,8.8, 3.9 Hz, 1H), 6.68 (s, 1H), 3.65 (t, J=4.7 Hz, 4H), 3.13-2.90 (m,4H). ES/MS m/z=501.1 (M+H)⁺.

Step 7:8-chloro-N-(5-morpholino-2-nitro-3-(1-trityl-1H-imidazol-4-yl)phenyl)quinolin-4-amine

To a solution ofN-(3-bromo-5-morpholino-2-nitrophenyl)-8-chloroquinolin-4-amine (250 mg,0.54 mmol) in dioxane (3 mL) was added4-(tri-n-butylstannyl)-1-tritylimidazole (355 mg, 0.59 mmol), copperiodide (10 mg, 0.05 mmol), and Pd(II)Cl₂dppf (35 mg, 0.05 mmol). Theresulting mixture was degassed under Argon and heated to 80° C. After 18hours the reaction was allowed to cool and was purified directly onsilica (0-100% EtOAc/DCM) to give8-chloro-N-(5-morpholino-2-nitro-3-(1-trityl-1H-imidazol-4-yl)phenyl)quinolin-4-amine.ES/MS m/z 693.2. (M+H)⁺.

Step 8:4-(l-(8-chloroquinolin-4-yl)-4-(1H-imidazol-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine

Formaldehyde (0.11 mL, 1.3 mmol) was added to a suspension of8-chloro-N-(5-morpholino-2-nitro-3-(1-trityl-1H-imidazol-4-yl)phenyl)quinolin-4-amine(150 mg, 0.22 mmol) and sodium thiosulfite (113 mg, 0.65 mmol) in amixture of EtOH (1 mL) and DMSO (1 mL). The vessel was sealed and heatedto 80° C. for 18 hours. After cooling, the mixture was poured into EtOAcand washed with water, then aq. NaHCO₃. The organic phase was purifiedon silica (0-30% MeOH/DCM), then by prep LC, to give4-(1-(8-chloroquinolin-4-yl)-4-(1H-imidazol-4-yl)-1H-benzo[d]imidazol-6-yl)morpholine(Compound 332). 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.27 (d, J=4.5Hz, 1H), 8.68 (m, 1H), 8.57 (m, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.96 (d,J=4.6, 1H), 7.69-7.60 (m, 2H), 7.50 (d, J=8.5 Hz, 1H), 6.76 (d, J=2.0Hz, 1H), 3.71 (t, J=4.8 Hz, 4H), 3.13-3.08 (m, 4H). ES/MS m/z 431.1(M+H)⁺.

The compounds listed in the table below were prepared in a mannersimilar to that described above using appropriate intermediates andchemistry.

Compound Name MS NMR 331 4-[3-(8-chloroquinolin- 459.11 1H NMR (400 MHz,DMSO-d6) δ 4-yl)-2-ethyl-7-(1H- 9.34-9.27 (m, 2H), 8.57 (d, J = 1.5,imidazol-4- 1H), 8.11 (d, J = 7.5 Hz, 1H), yl)benzimidazol-5- 7.97 (d, J= 4.6 Hz, 1H), yl]morpholine 7.65-7.57 (m, 1H), 7.55 (d, J = 2.4 Hz,1H), 7.18 (d, J = 8.4 Hz, 1H), 6.53-6.47 (m, 1H), 3.67 (t, J = 4.8 Hz,4H), 3.10-2.96 (m, 4H), 2.75-2.52 (m, 2H), 1.21 (t, J = 7.5 Hz, 3H). 3324-[3-(8-chloroquinolin- 431.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-7-(1H-imidazol-4- 9.29 (s, 1H), 9.27 (d, J = 4.5 Hz,yl)benzimidazol-5- 1H), 8.68 (m, 1H), 8.57 (m, 1H), yl]morpholine 8.13(d, J = 7.5 Hz, 1H), 7.96 (d, J = 4.6, 1H), 7.69-7.60 (m, 2H), 7.50 (d,J = 8.5 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 3.71 (t, J = 4.8 Hz, 4H),3.13-3.08 (m, 4H). 333 4-[3-(5,8-dichloro-2- 493.17 1H NMR (400 MHz,DMSO-d6) δ methylquinolin-4-yl)-7- 9.25 (s, 1H), 8.51 (s, 1H), 8.05 (d,J = 8.3 Hz, (1H-imidazol-5-yl)-2- 1H), 7.84 (s, 1H), 7.66 (d,methylbenzimidazol-5- J = 8.3 Hz, 1H), 7.48 (d, J = 2.1 Hz,yl]morpholine 1H), 6.57 (d, J = 1.8 Hz, 1H), 3.69 (t, J = 4.7 Hz, 4H),3.12-3.00 (m, 4H), 2.83 (s, 3H), 2.31 (s, 3H). 334 4-[3-(5,8-dichloro-2-507.2 1H NMR (400 MHz, DMSO-d6) δ methylquinolin-4-yl)-2- 9.27 (d, J =1.3 Hz, 1H), 8.54 (d, J = 1.3 Hz, ethyl-7-(1H-imidazol-5- 1H), 8.04 (d,J = 8.3 Hz, yl)benzimidazol-5- 1H), 7.84 (s, 1H), 7.65 (d, J = 8.3 Hz,yl]morpholine 1H), 7.49 (d, J = 2.1 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H),3.69 (t, J = 4.7 Hz, 4H), 3.12-2.99 (m, 4H), 2.82 (s, 3H), 2.64-2.51 (m,2H), 1.26 (t, J = 7.4 Hz, 3H). 335 4-[3-(5,8- 447.26 1H NMR (400 MHz,DMSO-d6) δ difluoroquinolin-4-yl)- 9.29 (d, J = 4.5 Hz, 1H), 9.26 (d, J= 1.4 Hz, 7-(1H-imidazol-5-yl)-2- 1H), 8.51 (d, J = 1.3 Hz,methylbenzimidazol-5- 1H), 7.96 (d, J = 4.5 Hz, 1H), yl]morpholine 7.78(ddd, J = 10.2, 8.8, 4.2 Hz, 1H), 7.52-7.40 (m, 2H), 6.62 (d, J = 2.1Hz, 1H), 3.69 (t, J = 4.8 Hz, 4H), 3.12-3.02 (m, 4H), 2.35 (s, 3H). 3364-[3-(5,8- 433.24 1H NMR (400 MHz, DMSO-d6) δ difluoroquinolin-4-yl)-9.28 (d, J = 1.4 Hz, 2H), 9.24 (d, J = 4.5 Hz, 7-(1H-imidazol-5- 1H),8.61 (d, J = 2.6 Hz, yl)benzimidazol-5- 1H), 8.55 (d, J = 1.4 Hz, 1H),yl]morpholine 7.96 (d, J = 4.6 Hz, 1H), 7.79 (ddd, J = 10.1, 8.7, 4.1Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.49 (ddt, J = 12.4, 8.8, 4.5 Hz,1H), 6.84 (d, J = 2.1 Hz, 1H), 3.72 (t, J = 4.7 Hz, 4H), 3.19-3.05 (m,4H). 337 4-[3-(5,8- 461.19 1H NMR (400 MHz, DMSO-d6) δdifluoroquinolin-4-yl)- 9.31-9.25 (m, 2H), 8.56-8.51 (m,2-ethyl-7-(1H-imidazol- 1H), 7.97 (d, J = 4.6 Hz, 1H),5-yl)benzimidazol-5- 7.78 (td, J = 9.3, 8.9, 4.0 Hz, 1H), yl]morpholine7.51 (d, J = 2.0 Hz, 1H), 7.45 (ddd, J = 12.2, 8.7, 3.7 Hz, 1H), 6.61(d, J = 1.9 Hz, 1H), 3.69 (t, J = 4.8 Hz, 4H), 3.10-3.02 (m, 4H),2.72-2.52 (m, 2H), 1.23 (t, J = 7.5 Hz, 3H).

Separation of atropisomers: The atropisomers of compound 200 wereseparated on OD-H SFC 5 uM 21×250 mm column in 30% EtOH/CO2 at 60 mL/minto give the atropisomers of4-[3-(8-fluoroquinolin-4-yl)-2-methyl-7-(1,3-oxazol-2-yl)benzimidazol-5-yl]morpholine,Compound 340 and Compound 341. 1H NMR (400 MHz, DMSO-d6) δ 9.27 (d,J=4.5 Hz, 1H), 8.42 (d, J=0.8 Hz, 1H), 8.01 (d, J=4.5 Hz, 1H), 7.77(ddd, J=10.9, 7.8, 1.2 Hz, 1H), 7.69-7.59 (m, 2H), 7.56 (d, J=0.8 Hz,1H), 7.24 (d, J=8.4 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 3.66 (t, J=4.7 Hz,4H), 3.12-2.95 (m, 4H), 2.45 (s, 3H). ES/MS m/z 430.1 (M+H)⁺.

The compounds listed in the table below were prepared in a mannersimilar to that described above using appropriate intermediates andchemistry.

Compound Name MS NMR 342 4-[7-(2-chloro-1H- 507.2 1H NMR (400 MHz,DMSO-d6) δ imidazol-5-yl)-2- 12.89 (s, 1H), 9.27 (d, J = 4.5 Hz,cyclopropyl-3-(5,8- 1H), 8.09 (s, 1H), 7.97 (d, J = 4.5 Hz,difluoroquinolin-4- 1H), 7.76 (td, J = 9.3, 4.1 Hz, yl)benzimidazol-5-1H), 7.46 (ddd, J = 12.3, 8.7, 3.8 Hz, yl]morpholine 1H), 7.39 (s, 1H),6.40 (d, J = 2.2 Hz, 1H), 3.67 (t, J = 4.7 Hz, 4H), 3.04-2.96 (m, 4H),1.59 (td, J = 8.3, 4.2 Hz, 1H), 1.22-0.99 (m, 2H), 0.94-0.74 (m, 2H).343 4-[7-(2-chloro-1H- 507.2 1H NMR (400 MHz, DMSO-d6) δimidazol-5-yl)-2- 13.19-12.81 (m, 1H), 9.27 (d, J = 4.5 Hz,cyclopropyl-3-(5,8- 1H), 8.13 (s, 1H), 7.97 (d, J = 4.5 Hz,difluoroquinolin-4- 1H), 7.76 (ddd, J = 10.0, yl)benzimidazol-5- 8.7,4.1 Hz, 1H), 7.46 (ddd, J = 12.3, yl]morpholine 8.7, 3.8 Hz, 1H), 6.39(d, J = 2.1 Hz, 1H), 3.67 (t, J = 4.7 Hz, 4H), 3.03-2.97 (m, 4H), 1.59(td, J = 8.2, 4.2 Hz, 1H), 1.20-1.12 (m, 1H), 1.11-1.03 (m, 1H),0.95-0.75 (m, 2H). 344 4-[3-(5-chloro-8- 464.1 1H NMR (400 MHz, DMSO-d6)δ fluoroquinolin-4-yl)-2- 9.30 (d, J = 4.4 Hz, 1H), 8.00 (d, J = 4.4 Hz,methyl-7-(4H-1,2,4- 1H), 7.79 (d, J = 7.2 Hz, triazol-3- 2H), 7.63 (s,1H), 6.68 (s, 1H), yl)benzimidazol-5- 3.65 (dd, J = 6.0, 3.6 Hz, 4H),yl]morpholine 3.11-2.97 (m, 4H), 2.39 (s, 3H). 345 4-[3-(5-chloro-8-464.1 1H NMR (400 MHz, DMSO-d6) δ fluoroquinolin-4-yl)-2- 9.29 (d, J =4.4 Hz, 1H), 7.99 (d, J = 4.5 Hz, methyl-7-(4H-1,2,4- 1H), 7.79 (d, J =7.1 Hz, triazol-3- 2H), 7.61 (s, 1H), 6.67 (s, 1H), yl)benzimidazol-5-3.68-3.49 (m, 4H), 3.13-2.95 (m, 4H), yl]morpholine 2.38 (s, 3H). 3464-[7-(2-chloro-1H- 495.2 1H NMR (400 MHz, DMSO-d6) δimidazol-5-yl)-3-(5,8- 12.91 (s, 1H), 9.26 (d, J = 4.5 Hz,difluoroquinolin-4-yl)- 1H), 8.24 (d, J = 1.7 Hz, 1H),2-ethylbenzimidazol-5- 7.93 (d, J = 4.5 Hz, 1H), 7.76 (ddd, J = 9.9,yl]morpholine 8.8, 4.1 Hz, 1H), 7.50-7.38 (m, 2H), 6.35 (d, J = 2.3 Hz,1H), 3.71-3.62 (m, 4H), 3.06-2.95 (m, 4H), 2.65-2.51 (m, 2H), 1.20 (t, J= 7.5 Hz, 3H). 347 4-[7-(2-chloro-1H- 495.2 1H NMR (400 MHz, DMSO-d6) δimidazol-5-yl)-3-(5,8- 12.91 (s, 1H), 9.26 (d, J = 4.5 Hz,difluoroquinolin-4-yl)- 1H), 8.24 (s, 1H), 7.93 (d, J = 4.5 Hz,2-ethylbenzimidazol-5- 1H), 7.76 (td, J = 9.3, 4.1 Hz, yl]morpholine1H), 7.48-7.38 (m, 2H), 6.39-6.32 (m, 1H), 3.68-3.63 (m, 4H), 3.01-2.96(m, 4H), 2.61-2.51 (m, 2H), 1.20 (t, J = 7.5 Hz, 3H). 348 4-[3-(3,8-508.2 1H NMR (400 MHz, DMSO-d6) δ dichloroquinolin-4-yl)- 9.37 (s, 1H),8.11 (dd, J = 7.6, 1.2 Hz, 2-ethyl-7-(5-methyl-4H- 1H), 7.64 (dd, J =8.5, 7.6 Hz, 1,2,4-triazol-3- 1H), 7.52 (s, 1H), 7.15 (d, J = 8.4 Hz,yl)benzimidazol-5- 1H), 6.67 (s, 1H), 3.63 (t, J = 4.8 Hz, yl]morpholine4H), 3.00 (s, 4H), 2.97-2.74 (m, 2H), 2.37 (s, 3H), 1.30-1.16 (m, 3H).349 4-[3-(3,8- 508.1 1H NMR (400 MHz, DMSO-d6) δ dichloroquinolin-4-yl)-9.38 (s, 1H), 8.11 (dd, J = 7.6, 1.2 Hz, 2-ethyl-7-(5-methyl-4H- 1H),7.64 (dd, J = 8.5, 7.6 Hz, 1,2,4-triazol-3- 1H), 7.53 (d, J = 2.3 Hz,1H), yl)benzimidazol-5- 7.18 (dd, J = 8.5, 1.2 Hz, 1H), 6.65 (s,yl]morpholine 1H), 3.63 (s, 4H), 3.00 (s, 4H), 2.54 (dp, J = 7.6, 4.1Hz, 2H), 2.40 (s, 3H), 1.18 (t, J = 7.5 Hz, 3H). 350 (S)-4-(1-(5,8-462.2 1H NMR (400 MHz, DMSO-d6) δ difluoroquinolin-4-yl)- 9.28 (d, J =4.5 Hz, 1H), 7.97 (d, J = 4.5 Hz, 2-methyl-4-(5-methyl- 1H), 7.81-7.74(m, 1H), 4H-1,2,4-triazol-3-yl)- 7.52 (s, 1H), 7.47 (ddd, J = 12.3,1H-benzo[d]imidazol-6- 8.8, 3.8 Hz, 1H), 6.69 (s, 1H), yl)morpholine3.70-3.63 (m, 4H), 3.06-2.99 (m, 4H), 2.36 (s, 6H). 351 (R)-4-(1-(5,8-462.2 1H NMR (400 MHz, DMSO-d6) δ difluoroquinolin-4-yl)- 9.32 (d, J =4.5 Hz, 1H), 8.04 (d, J = 4.5 Hz, 2-methyl-4-(5-methyl- 1H), 7.84-7.75(m, 1H), 4H-1,2,4-triazol-3-yl)- 7.62 (s, 1H), 7.49 (ddd, J = 12.2,1H-benzo[d]imidazol-6- 8.8, 3.7 Hz, 1H), 6.74 (s, 1H), yl)morpholine3.70-3.63 (m, 4H), 3.06 (t, J = 4.9 Hz, 4H), 2.48-2.42 (m, 6H). 3524-[3-(7,8- 448.2 1H NMR (400 MHz, DMSO-d6) δ difluoroquinolin-4-yl)-9.29 (d, J = 4.5 Hz, 1H), 7.99 (d, J = 4.5 Hz, 2-methyl-7-(4H-1,2,4-1H), 7.87-7.72 (m, 1H), triazol-3- 7.67 (s, 1H), 7.32 (s, 1H), 6.62 (d,J = 2.2 Hz, yl)benzimidazol-5- 1H), 3.64 (t, J = 4.7 Hz, yl]morpholine5H), 3.01 (d, J = 4.1 Hz, 2H), 2.46 (s, 3H). 353 4-[3-(7,8- 448.2 1H NMR(400 MHz, DMSO-d6) δ difluoroquinolin-4-yl)- 9.29 (d, J = 4.5 Hz, 1H),7.98 (d, J = 4.5 Hz, 2-methyl-7-(4H-1,2,4- 1H), 7.77 (td, J = 9.8, 7.2Hz, triazol-3- 1H), 7.66 (s, 1H), 7.30 (s, 1H), yl)benzimidazol-5- 6.62(d, J = 2.2 Hz, 1H), 3.64 (t, J = 4.7 Hz, yl]morpholine 4H), 3.09-2.95(m, 4H), 2.44 (s, 3H). 354 4-[3-(8-fluoroquinolin- 458.2 1H NMR (400MHz, DMSO-d6) δ 4-yl)-2-propyl-7-(4H- 9.24 (d, J = 4.5 Hz, 1H), 8.00 (d,J = 4.5 Hz, 1,2,4-triazol-3- 1H), 7.63 (dd, J = 13.3, 5.0 Hz,yl)benzimidazol-5- 2H), 6.58 (s, 1H), 3.64 (t, J = 4.7 Hz, yl]morpholine4H), 3.00 (d, J = 3.8 Hz, 4H), 2.66 (d, J = 6.6 Hz, 2H), 1.63 (s, 2H),0.78 (t, J = 7.4 Hz, 3H). 355 4-[3-(8-fluoroquinolin- 458.2 1H NMR (400MHz, DMSO-d6) δ 4-yl)-2-propyl-7-(4H- 9.26 (d, J = 4.5 Hz, 1H), 8.48 (s,1,2,4-triazol-3- 1H), 8.03 (d, J = 4.5 Hz, 1H), yl)benzimidazol-5-7.85-7.45 (m, 3H), 7.19 (s, 1H), 6.60 (d, yl]morpholine J = 2.2 Hz, 1H),3.64 (t, J = 4.8 Hz, 4H), 3.02 (q, J = 3.9 Hz, 4H), 2.84-2.52 (m, 2H),1.72-1.30 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H). 356 4-[3-(5,8- 476.2 1H NMR(400 MHz, DMSO-d6) δ difluoroquinolin-4-yl)- 9.27 (d, J = 4.5 Hz, 1H),8.35 (d, J = 0.8 Hz, 7-(1,3-oxazol-2-yl)-2- 1H), 7.97 (d, J = 4.5 Hz,propylbenzimidazol-5- 1H), 7.77 (ddd, J = 10.0, 8.8, 4.2 Hz,yl]morpholine 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.51-7.40 (m, 2H), 6.69 (d,J = 2.3 Hz, 1H), 3.69-3.62 (m, 4H), 3.06-2.98 (m, 4H), 2.68-2.51 (m,2H), 1.67-1.53 (m, 2H), 0.81 (t, J = 7.4 Hz, 3H). 357 4-[3-(5,8- 476.21H NMR (400 MHz, DMSO-d6) δ difluoroquinolin-4-yl)- 9.27 (d, J = 4.5 Hz,1H), 8.35 (d, J = 0.8 Hz, 7(1,3-oxazol-2-yl)-2- 1H), 7.97 (d, J = 4.5Hz, propylbenzimidazol-5- 1H), 7.77 (ddd, J = 10.0, 8.8, 4.2 Hz,yl]morpholine 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.49-7.41 (m, 2H), 6.69 (d,J = 2.3 Hz, 1H), 3.69-3.62 (m, 4H), 3.06-2.98 (m, 4H), 2.69-2.51 (m,2H), 1.65-1.54 (m, 2H), 0.81 (t, J = 7.4 Hz, 3H). 3584-[3-(8-chloroquinolin- 480.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-7-(5-chloro-4H- 9.29 (d, J = 4.5 Hz, 1H), 8.09 (dd, J = 7.5,1,2,4-triazol-3-yl)-2- 1.2 Hz, 1H), 7.96 (d, J = 4.5 Hz,methylbenzimidazol-5- 1H), 7.59 (dd, J = 8.5, 7.5 Hz, yl]morpholine 1H),7.50 (d, J = 2.2 Hz, 1H), 7.22 (dd, J = 8.5, 1.2 Hz, 1H), 6.63 (d, J =2.3 Hz, 1H), 3.63 (t, J = 4.7 Hz, 4H), 3.07-2.93 (m, 4H), 2.36 (s, 3H).359 4-[3-(8-chloroquinolin- 480.1 1H NMR (400 MHz, DMSO-d6) δ4-yl)-7-(5-chloro-4H- 9.29 (d, J = 4.5 Hz, 1H), 8.09 (dd, J = 7.5,1,2,4-triazol-3-yl)-2- 1.2 Hz, 1H), 7.96 (d, J = 4.5 Hz,methylbenzimidazol-5- 1H), 7.59 (dd, J = 8.5, 7.6 Hz, yl]morpholine 1H),7.50 (d, J = 2.2 Hz, 1H), 7.22 (dd, J = 8.5, 1.2 Hz, 1H), 6.63 (d, J =2.2 Hz, 1H), 3.63 (t, J = 4.7 Hz, 4H), 3.00 (q, J = 4.0 Hz, 4H), 2.36(s, 3H). 360 4-[3-(8-chloroquinolin- 446.2 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7-(4H- 9.37 (dd, J = 4.5, 0.6 Hz, 1H), 1,2,4-triazol-3-8.77 (s, 1H), 8.15 (dd, J = 7.4, 1.3 Hz, yl)benzimidazol-5- 1H), 8.09(d, J = 4.5 Hz, 1H), yl]morpholine 7.83 (d, J = 2.3 Hz, 1H), 7.64 (dd, J= 8.4, 7.5 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H),3.66 (t, J = 4.8 Hz, 4H), 3.08 (q, J = 3.9 Hz, 4H), 2.59 (s, 3H). 3614-[3-(8-chloroquinolin- 446.2 1H NMR (400 MHz, DMSO-d6) δ4-yl)-2-methyl-7-(4H- 9.37 (dd, J = 4.5, 0.6 Hz, 1H), 1,2,4-triazol-3-8.77 (s, 1H), 8.15 (dd, J = 7.4, 1.3 Hz, yl)benzimidazol-5- 1H), 8.09(d, J = 4.5 Hz, 1H), yl]morpholine 7.83 (d, J = 2.3 Hz, 1H), 7.64 (dd, J= 8.4, 7.5 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H),3.66 (t, J = 4.8 Hz, 4H), 3.08 (q, J = 3.9 Hz, 4H), 2.59 (s, 3H). 3624-[2-methyl-3-(5- 426.2 1H NMR (400 MHz, DMSO-d6) δmethylquinolin-4-yl)-7- 9.21 (d, J = 4.4 Hz, 1H), 8.73 (s,(4H-1,2,4-triazol-3- 1H), 8.21-8.15 (m, 1H), yl)benzimidazol-5-7.90-7.80 (m, 3H), 7.57-7.50 (m, 1H), yl]morpholine 6.69 (d, J = 2.2 Hz,1H), 3.67 (t, J = 4.8 Hz, 4H), 3.15-3.07 (m, 4H), 2.55 (s, 3H), 1.82 (s,3H). 363 4-[2-methyl-3-(5- 426.2 1H NMR (400 MHz, DMSO-d6) δmethylquinolin-4-yl)-7- 9.21 (d, J = 4.4 Hz, 1H), 8.73 (s,(4H-1,2,4-triazol-3- 1H), 8.21-8.15 (m, 1H), yl)benzimidazol-5-7.90-7.80 (m, 3H), 7.57-7.50 (m, 1H), yl]morpholine 6.69 (d, J = 2.2 Hz,1H), 3.67 (t, J = 4.8 Hz, 4H), 3.15-3.07 (m, 4H), 2.55 (s, 3H), 1.82 (s,3H). 364 4-(2-ethyl-6- 465.2 1H NMR (400 MHz, DMSO-d6) δmorpholino-4-(4H- 9.34 (d, J = 0.5 Hz, 1H), 8.54 (s,1,2,4-triazol-3-yl)-1H- 1H), 8.43 (dd, J = 7.2, 1.3 Hz, 1H),benzo[d]imidazol-1-yl)- 7.76-7.67 (m, 2H), 7.60 (d, J = 8.4 Hz,3-methylquinoline-8- 1H), 6.64 (d, J = 2.3 Hz, 1H), carbonitrile 3.64(t, J = 4.8 Hz, 4H), 3.05 (dd, J = 6.3, 3.8 Hz, 4H), 2.67 (d, J = 8.1Hz, 2H), 2.21 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H). 365 4-(2-ethyl-6- 465.21H NMR (400 MHz, DMSO-d6) δ morpholino-4-(4H- 9.34 (d, J = 0.5 Hz, 1H),8.54 (s, 1,2,4-triazol-3-yl)-1H- 1H), 8.43 (dd, J = 7.2, 1.3 Hz, 1H),benzo[d]imidazol-1-yl)- 7.76-7.67 (m, 2H), 7.60 (d, J = 8.4 Hz,3-methylquinoline-8- 1H), 6.64 (d, J = 2.3 Hz, 1H), carbonitrile 3.64(t, J = 4.8 Hz, 4H), 3.05 (dd, J = 6.3, 3.8 Hz, 4H), 2.67 (d, J = 8.1Hz, 2H), 2.21 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H). 366 4-(1-(3,8- 494.1 1HNMR (400 MHz, DMSO-d6) δ dichloroquinolin-4-yl)- 9.42 (s, 1H), 8.14 (dd,J = 7.6, 1.2 Hz, 2-methyl-4-(5-methyl- 1H), 7.71-7.62 (m, 2H),4H-1,2,4-triazol-3-yl)- 7.38 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 2.3 Hz,1H-benzo[d]imidazol-6- 1H), 3.72-3.58 (m, 4H), yl)morpholine 3.04 (dd, J= 6.1, 3.8 Hz, 4H), 2.48 (s, 3H), 2.44 (s, 3H). 367 4-(1-(3,8- 494.1 1HNMR (400 MHz, DMSO-d6) δ dichloroquinolin-4-yl)- 9.42 (s, 1H), 8.14 (dd,J = 7.6, 1.2 Hz, 2-methyl-4-(5-methyl- 1H), 7.71-7.62 (m, 2H),4H-1,2,4-triazol-3-yl)- 7.38 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 2.3 Hz,1H-benzo[d]imidazol-6- 1H), 3.72-3.58 (m, 4H), yl)morpholine 3.04 (dd, J= 6.1, 3.8 Hz, 4H), 2.48 (s, 3H), 2.44 (s, 3H). 368 4-(1-(5,8- 475.2 1HNMR (400 MHz, DMSO-d6) δ difluoroquinolin-4-yl)- 9.26 (d, J = 4.5 Hz,1H), 7.94 (d, J = 4.5 Hz, 2-propyl-4-(1H-pyrazol- 1H), 7.76 (ddd, J =10.0, 5-yl)-1H- 8.8, 4.2 Hz, 1H), 7.71 (br s, 1H), benzo[d]imidazol-6-7.45 (ddd, J = 12.5, 8.8, 3.8 Hz, yl)morpholine 1H), 7.39 (br s, 2H),6.44 (d, J = 2.1 Hz, 1H), 3.67 (t, J = 4.7 Hz, 4H), 3.05-2.98 (m, 4H),2.60-2.51 (m, 2H), 1.69 (h, J = 7.4 Hz, 2H), 0.86 (t, J = 7.4 Hz, 3H).369 4-(1-(5,8- 475.2 1H NMR (400 MHz, DMSO-d6) δ difluoroquinolin-4-yl)-13.27-12.80 (m, 1H), 9.26 (d, J = 4.5 Hz, 2-propyl-4-(1H-pyrazol- 1H),7.94 (d, J = 4.5 Hz, 5-yl)-1H- 1H), 7.76 (ddd, J = 10.1, 8.9, 4.2 Hz,benzo[d]imidazol-6- 1H), 7.85-7.59 (m, 1H), yl)morpholine 7.49-7.41 (m,1H), 7.58-7.24 (m, 1H), 6.44 (s, 1H), 3.67 (t, J = 4.7 Hz, 4H),3.04-2.97 (m, 4H), 2.56 (t, J = 7.4 Hz, 2H), 1.69 (q, J = 7.4 Hz, 2H),0.86 (t, J = 7.4 Hz, 3H) 370 4-(1-(5,8- 461.2 1H NMR (400 MHz, DMSO-d6)δ difluoroquinolin-4-yl)- 12.21 (s, 1H), 9.28 (d, J = 4.5 Hz,2-ethyl-4-(1H-imidazol- 1H), 7.99 (d, J = 4.5 Hz, 1H), 2-yl)-1H- 7.77(ddd, J = 10.0, 8.8, 4.2 Hz, 1H), benzo[d]imidazol-6- 7.60 (d, J = 2.3Hz, 1H), 7.46 (ddd, yl)morpholine J = 12.4, 8.8, 3.8 Hz, 1H), 7.37 (dd,J = 2.1, 1.2 Hz, 1H), 7.09 (t, J = 1.4 Hz, 1H), 6.53 (d, J = 2.3 Hz,1H), 3.70-3.63 (m, 4H), 3.05-2.98 (m, 4H), 2.71-2.53 (m, 2H), 1.26 (t, J= 7.5 Hz, 3H). 371 4-(1-(5,8- 461.2 1H NMR (400 MHz, DMSO-d6) δdifluoroquinolin-4-yl)- 12.28 (s, 1H), 9.28 (d, J = 4.5 Hz,2-ethyl-4-(1H-imidazol- 1H), 7.99 (d, J = 4.5 Hz, 1H), 2-yl)-1H- 7.77(ddd, J = 10.0, 8.8, 4.2 Hz, 1H), benzo[d]imidazol-6- 7.61 (d, J = 2.3Hz, 1H), 7.46 (ddd, yl)morpholine J = 12.4, 8.8, 3.8 Hz, 1H), 7.26 (brs, 2H), 6.53 (d, J = 2.3 Hz, 1H), 3.70-3.63 (m, 4H), 3.06-2.98 (m, 4H),2.68-2.57 (m, 2H), 1.25 (t, J = 7.5 Hz, 3H). 372 4-(4-(2-chloro-1H-481.18 1H NMR (400 MHz, DMSO-d6) δ imidazol-5-yl)-1-(5,8- 9.29 (d, J =4.5 Hz, 1H), 8.15 (s, difluoroquinolin-4-yl)- 1H), 7.97 (d, J = 4.5 Hz,1H), 2-methyl-1H- 7.78 (ddd, J = 10.0, 8.9, 4.2 Hz, 1H),benzo[d]imidazol-6- 7.53-7.44 (m, 1H), 7.44 (s, 1H), yl)morpholine 6.45(s, 1H), 3.67 (t, J = 4.7 Hz, 4H), 3.07-2.99 (m, 4H), 2.38 (s, 3H). 3734-(4-(2-chloro-1H- 481.2 1H NMR (400 MHz, DMSO-d6) δimidazol-5-yl)-1-(5,8- 9.29 (d, J = 4.5 Hz, 1H), 8.15 (s,difluoroquinolin-4-yl)- 1H), 7.97 (d, J = 4.5 Hz, 1H), 2-methyl-1H- 7.78(ddd, J = 10.0, 8.8, 4.2 Hz, 1H), benzo[d]imidazol-6- 7.53-7.44 (m, 1H),7.44 (s, 1H), yl)morpholine 6.45 (s, 1H), 3.67 (t, J = 4.7 Hz, 4H),3.13-2.91 (m, 4H), 2.38 (s, 3H). 374 3-methyl-4-(2-methyl-6- 451.2 1HNMR (400 MHz, DMSO-d6) δ morpholino-4-(4H- 9.35 (d, J = 0.5 Hz, 1H),8.61 (s, 1,2,4-triazol-3-yl)-1H- 1H), 8.44 (dd, J = 7.1, 1.4 Hz, 1H),benzo[d]imidazol-1- 7.87-7.60 (m, 3H), 6.68 (d, J = 2.3 Hz,yl)quinoline-8- 1H), 3.64 (t, J = 4.7 Hz, 4H), carbonitrile 3.06 (dd, J= 6.2, 3.7 Hz, 4H), 2.44 (s, 3H), 2.23 (s, 3H). 3753-methyl-4-(2-methyl-6- 451.2 1H NMR (400 MHz, DMSO-d6) δmorpholino-4-(4H- 9.35 (d, J = 0.5 Hz, 1H), 8.61 (s,1,2,4-triazol-3-yl)-1H- 1H), 8.44 (dd, J = 7.1, 1.4 Hz, 1H),benzo[d]imidazol-1- 7.87-7.60 (m, 3H), 6.68 (d, J = 2.3 Hz,yl)quinoline-8- 1H), 3.64 (t, J = 4.7 Hz, 4H), carbonitrile 3.06 (dd, J= 6.2, 3.7 Hz, 4H), 2.44 (s, 3H), 2.23 (s, 3H).

5-(1-(5,8-Difluoroquinolin-4-yl)-6-morpholino-1H-benzo[d]imidazol-4-yl)-1H-imidazole-2-carbonitrile

4-(1-(5,8-difluoroquinolin-4-yl)-4-(2-(trifluoromethyl)-1H-imidazol-5-yl)-1H-benzo[d]imidazol-6-yl)morpholine(26 mg, 0.042 mmol) was combined with NH₄OH (5% aqueous solution) andstirred at 50° C. for 12 days. The reaction was poured into water andextracted 3 times with DCM. The combined extracts were purified by HPLCeluting with 5-95% water/acetonitrile (0.1% v/v trifluoroacetic acid) togive the title compound (Compound 394). 1H NMR (400 MHz, DMSO-d6) δ 9.23(d, J=4.5 Hz, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 7.96 (d, J=4.6 Hz, 1H),7.78 (ddd, J=10.0, 8.7, 4.1 Hz, 1H), 7.65-7.59 (m, 1H), 7.48 (ddd,J=12.4, 8.8, 3.9 Hz, 1H), 6.76 (d, J=2.2 Hz, 1H), 3.71 (t, J=4.7 Hz,4H), 3.17-3.04 (m, 4H). ES/MS m/z=458.2 (M+H)⁺.

tert-Butyl 4-(4-chloroquinolin-2-yl)piperazine-1-carboxylate

A suspension of 2,4-dichloroquinoline (6.4 g, 32.2 mmol), tert-butylpiperazine-1-carboxylate (5.0 g, 26.8 mmol) and diethylisopropylamine(6.5 mL, 38.0 mmol) was stirred in a sealed tube at 100° C. for 2 days.Upon cooling, the reaction mixture was concentrated in vacuuo to affordmaterial which was purified by column chromatography on SiO₂ elutingwith EtOAc in hexanes (0-15%) to afford the title compound. ES/MSm/z=348.1 (M+H)⁺.

4-Chloro-2-(1-trityl-1H-pyrazol-3-yl)quinoline

A sealed tube was charged with 2,4-dichloroquinoline (1.0 g, 5.05 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazole(2.2 g, 5.05 mmol), K₃PO₄ (3.2 g, 15.1 mmol) and Pd(PPh₃)₄(0.58 g, 0.50mmol) followed by dioxane (50 mL) and water (12 mL). The reactionmixture was stirred at 90° C. for 3 h. Upon cooling, the reactionmixture was absorbed on SiO₂ followed by purification on columnchromatography on SiO₂ eluting with EtOAc in hexanes (0-100%) to affordthe title compound. ES/MS m/z=472.2 (M+H)+.

The compound listed below was prepared in a similar manner usingappropriate intermediates:

-   4-chloro-2-(1-trityl-1H-pyrazol-4-yl)quinoline

2-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy methyl)-1H-imidazole

Sodium hydride (60% in mineral oil, 764 mg, 19.1 mmol) was slowly addedto a solution of 2-(trifluoromethyl)imidazole (650 mg, 4.78 mmol) in THF(25 mL) at 0° C. under N2. The mixture was stirred at 0° C. for 2 hours,then 2-(trimethylsilyl)ethoxymethyl chloride (1.0 mL, 5.73 mmol) wasadded. The reaction was allowed to gradually attain ambient temperatureand stir overnight. The reaction was quenched slowly with water, thenpoured into EtOAc. The organic phase was washed with water, brine, thenpurified on silica gel (40 g column, 0-100% EtOAc/hexanes) to give thetitle compound. ES/MS m/z=267.1 (M+H)⁺.

Biological Examples

The compounds of formula (I) were characterized for their enzymaticactivity against the PI3K isoforms. The activities were measured using atime-resolved fluorescence resonance energy transfer (TR-FRET) assay.TR-FRET monitored the formation of 3,4,5-inositol triphosphate moleculethat competed with fluorescently labeled PIP3 for binding to the GRP-1pleckstrin homology domain protein. An increase in phosphatidylinositide3-phosphate product resulted in a decrease in TR-FRET signal as thelabeled fluorophore was displaced from the GRP-1 protein binding site.

Class I PI3K isoforms were expressed and purified as heterodimericrecombinant proteins. All assay reagents and buffers for the TR-FRETassay were purchased from Millipore. PI3K isoforms were assayed underinitial rate conditions in the presence of 25 mM Hepes (pH 7.4), and 2×Km ATP (75-500 μM), 2 μM PIP2, 5% glycerol, 5 mM MgCl₂, 50 mM NaCl,0.05% (v/v) Chaps, 1 mM dithiothreitol, and 1% (v/v) DMSO at thefollowing concentrations for each isoform: PI3Kα, PI3Kβ, and PI3Kδbetween 25 and 50 μM, and PI3Kγ at 2 nM. The compounds were added to theassay solution and incubated for 30 minutes at 25° C. The reactions wereterminated with a final concentration of 10 mM EDTA, 10 nM labeled-PIP3,and 35 nM Europium labeled GRP-1 detector protein before reading TR-FRETon an Envision plate reader (Ex: 340 nm; Em: 615/665 nm; 100 μs delayand 500 μs read window).

The results were normalized based on positive (1 μM wortmanin) andnegative (DMSO) controls, and the IC₅₀ values for PI3K α, β, δ, and γwere calculated from the fit of the dose-response curves to afour-parameter equation. These assays generally produced results within3-fold of the reported mean. As shown in Table 1, the compounds providedherein are inhibitors of PI3Kβ.

The compounds of formula (I) were also characterized for their metabolicstability in human hepatocytes by incubating the test articles (TA) incryopreserved human hepatocytes and monitoring parent drug disappearancevia LC/MC. The TA was incubated with 1 million hepatocytes/mL at 2 μMsubstrate in duplicate. The incubation was carried out at 37° C. with 5%CO₂ and saturating humidity. Samples were taken at 0, 1, 2, and 4 hoursto monitor the disappearance of TA and a half-life (t_(1/2)) wasdetermined.

TABLE 1 example IC₅₀-PIP-β (nM) 1 4 2 24 3 24 4 28 5 29 6 31 7 31 8 32 933 10 41 11 42 12 43 13 45 14 49 15 49 16 53 17 60 18 63 19 110 20 12021 130 22 280 23 390 24 1500 25 2200 26 22 27 56 28 3 29 7 30 8 31 9 329 33 10 34 10 35 11 36 11 37 11 38 11 39 11 40 22 41 21 42 20 43 20 4419 45 19 46 19 47 18 48 18 49 18 50 16 51 15 52 15 53 15 54 14 55 27 5672 57 55 58 62 59 130 60 30 61 27 62 23 63 28 64 21 65 24 66 16 67 99 688 69 17 70 36 71 23 72 25 73 78 74 62 75 29 76 29 77 97 78 27 79 110 8061 81 11 82 9 83 19 84 17 85 280 86 16 87 14 88 4 89 12 90 11 91 19 9246 93 290 94 26 95 6 96 24 97 12 98 13 99 33 100 43 101 7 102 21 103 9104 84 105 10 106 17 107 29 108 26 109 13 110 19 111 3 112 17 113 17 11412 115 14 116 21 117 15 118 52 119 24 120 27 121 44 122 13 123 110 124 9125 16 126 21 127 23 128 51 129 23 130 87 131 46 132 380 133 21 134 16135 43 136 48 137 17 138 140 139 14 140 13 141 10 142 15 143 84 144 65145 56 146 101 149 100 150 27 151 44 152 59 153 120 154 2200 155 20 15620 157 47 160 470 161 23 162 77 163 630 164 130 165 720 166 480 167 12168 9 169 16 170 7 171 100 172 100 173 140 174 13 175 10 176 510 177 230178 12 179 44 180 42 181 210 182 34 183 170 198 120 199 610 200 9 201 19202 >10000 203 120 204 8 205 12 206 40 207 13 208 14 209 15 210 27 21122 212 34 213 16 214 56 215 630 216 380 217 9 218 11 219 8 220 7 221 11222 12 223 9 224 3 225 18 226 5 227 10 228 10 229 5 230 7 231 16 232 56233 8 234 100 235 17 236 5 237 50 238 4 239 12 240 2 241 27 242 6 243 26244 9 245 21 246 1100 247 12 260 22 261 24 262 27 263 13 264 770 265 460266 11 267 2100 268 317 269 7000 270 36 271 46 272 65 273 2600 274 27275 88 276 420 277 620 278 4 279 10 280 13 281 15 282 25 283 71 284 13285 4 286 14 287 56 288 5 289 24 290 68 291 27 292 42 293 38 294 6 29512 296 17 297 3800 298 10 299 17 300 14 301 20 302 24 303 21 304 81 30513 306 370 307 8 308 6 309 50 310 36 311 47 312 967 313 9800 314 7800315 490 316 2500 317 690 318 5200 319 8600 320 >10000 321 4400322 >10000 323 417 329 7 330 5 331 7 332 2 333 9 334 24 335 15 336 5 33720 340 1900 341 6 342 >10000 343 5 344 5 345 4462 346 10000 347 7 348 13349 439 350 10 351 460 352 7 353 270 354 8 355 2500 356 >10000 357 5 35810 359 1200 360 2800 361 2 362 28 363 8000 364 25 365 9100 366 17 3675600 368 18 369 >10000 370 13 371 6800 372 6 373 1000 374 22 375 7100376 70 377 35 378 27 379 8 380 240 381 24 382 130 383 11 387 13 388 1100389 16 390 840 391 10 392 9 393 21 394 860

From the foregoing it will be appreciated that, although specificembodiments have been described herein for purposes of illustration,various modifications may be made without deviating from the spirit andscope of the present application.

What is claimed:
 1. A compound having the structure of formula (I):

wherein n is 1, 2, 3 or 4; m is 1, 2, 3 or 4; s is 1 or 2; t is 1 or 2; each R¹ is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a),—C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R¹⁰⁰; R² is selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R¹⁰¹; R³ is selected from C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; wherein each C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R¹⁰²; R⁴ is selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, acyl, C₃₋₈ cycloalkyl and C₁₋₆ alkyl sulfonyl; each R⁵ is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R¹⁰³; each R⁶ is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl; each R^(a) and R^(b) is independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, is optionally substituted with one to four R²⁰⁰; each R¹⁰⁰, R¹⁰¹, R¹⁰², and R¹⁰³ is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, is optionally substituted with one to four R²⁰¹; and, each R²⁰⁰ and R²⁰¹ is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(c), —C(O)OR^(d), —C(O)NR^(c)R^(d), —N(R^(c))C(O)R^(d), —S(O)NR^(d)R^(d), —S(O)₂NR^(c)R^(d), —S(O)R^(c), —S(O)₂R^(c), —NR^(c)R^(d), —OR^(c), —SR^(c), C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl; each R^(c) and R^(d) is independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl; or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 2. The compound of claim 1 having the structure of formula IB:

wherein

is a single or double bond; X¹ is N or C; each X², X³, X⁴ and X⁵ is independently selected from S, O, CR¹⁰ and NR¹¹; wherein each R¹⁰ is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R¹⁰⁴; wherein each R¹¹ is independently selected from absent, hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; alternatively, one R¹⁰ and one R¹¹ group, together with the atoms to which they are attached form a five, six or seven membered fused or bridged ring; each R¹⁰⁴ is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, is optionally substituted with one to four R²⁰¹; and each R²⁰¹ is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(c), —C(O)OR^(d), —C(O)NR^(c)R^(d), —N(R^(c))C(O)R^(d), —S(O)NR^(d)R^(d), —S(O)₂NR^(c)R^(d), —S(O)R^(c), —S(O)₂R, —NR^(c)R^(d), —OR^(c), —SR^(c), C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl; each R^(c) and R^(d) is independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl; or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 3. The compound of claim 1, wherein R³ is selected from:

wherein t is 1 or 2; wherein each R¹³ is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 4. The compound of claim 3 having the structure of formula IC:

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 5. The compound of claim 3 having the structure of formula ID:

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 6. The compound of claim 2 having the structure of formula IE:

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 7. The compound of claim 3 having the structure of formula IF:

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 8. The compound of claim 3 having the structure of formula IG:

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 9. A composition comprising an atropisomer of formula IE:

wherein n is 1, 2, 3 or 4; m is 1, 2, 3 or 4; s is 1 or 2;

is a single or double bond; X¹ is N or C; each X², X³, X⁴ and X⁵ is independently selected from S, O, CR ¹⁰ and NR¹¹ ; wherein each R¹⁰ is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b)—S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R¹⁰⁴; wherein each R¹¹ is independently selected from absent, hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; alternatively, one R¹⁰ and one R¹¹ group, together with the atoms to which they are attached form a five, six or seven membered fused or bridged ring; each R¹ is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R¹⁰⁰; R² is selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R¹⁰¹; R⁴ is selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, acyl, C₃₋₈ cycloalkyl and C₁₋₆ alkyl sulfonyl; each R⁵ is independently selected from hydrogen, halo, cyano, hydroxy, amino, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R¹⁰³; each R^(a) and R^(b) is independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl is optionally substituted with one to four R²⁰⁰; each R¹⁰⁰, R¹⁰¹, R103, and R¹⁰⁴ is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(a), —C(O)OR^(b), —C(O)NR^(a)R^(b), —N(R^(a))C(O)R^(b), —S(O)NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —S(O)R^(a), —S(O)₂R^(a), —NR^(a)R^(b), —OR^(a), —SR^(b), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl; wherein each C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl is optionally substituted with one to four R²⁰¹; and each R²⁰⁰ and R²⁰¹ is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, —C(O)R^(c), —C(O)OR^(d), —C(O)NR^(c)R^(d), —N(R^(c))C(O)R^(d), —S(O)NR^(d)R^(d), —S(O)₂NR^(c)R^(d), —S(O)R^(c), —S(O)₂R^(c), —NR^(c)R^(d), —OR^(c), —SR^(c), C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl; each R^(c) and R^(d) is independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl; or a pharmaceutically acceptable salt thereof, and a carrier; wherein the atropisomer of formula IE or a pharmaceutically acceptable salt thereof, is present in excess of its corresponding enantiomer or a pharmaceutically acceptable salt thereof.
 10. The compound of claim 2 having the structure of formula IH:

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 11. The compound of claim 3, having the structure of formula IJ:

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 12. The compound of claim 3, having the structure of formula IK:

or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 13. The compound of claim 1, wherein R¹ is independently selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, butyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl; or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 14. The compound of claim 1, wherein R² is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, 5-6 membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, and 4-6 membered heterocyclyl containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; wherein each C₁₋₆ alkyl, C₃₋₈ cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocyclyl is optionally substituted with one to four R¹⁰¹; or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 15. The compound of claim 1, wherein R⁴ is selected from hydrogen and methyl; or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 16. The compound of claim 1, wherein R⁵ is selected from hydrogen, methyl, ethyl, trifluoromethyl, carboxamide, cyano, piperazinyl, cyclopropyl, phenyl and triazolyl; or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 17. The compound of claim 1, wherein the compound is selected from: Example Structure 1

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or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 18. The compound of claim 1, wherein the compound is selected from the group consisting of: Compound No. Structure 341

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or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 19. The compound of claim 1, wherein the compound is selected from the group consisting of: Example Image 149

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or a pharmaceutically acceptable salt, isomer, or a mixture thereof.
 20. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt, isomer, or a mixture thereof, and at least one pharmaceutically acceptable vehicle. 